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Systematic Investigation of the Diagnostic and Prognostic Impact of LINC01087 in Human Cancers. Cancers (1) Background: Long non-coding RNAs may constitute epigenetic biomarkers for the diagnosis, prognosis, and therapeutic response of a variety of tumors. In this context, we aimed at assessing the diagnostic and prognostic value of the recently described long intergenic non-coding RNA 01087 (LINC01087) in human cancers. (2) Methods: We studied the expression of LINC01087 across 30 oncological indications by interrogating public resources. Data extracted from the TCGA and GTEx databases were exploited to plot receiver operating characteristic curves (ROC) and determine the diagnostic performance of LINC01087. Survival data from TCGA and KM-Plotter directories allowed us to graph Kaplan-Meier curves and evaluate the prognostic value of LINC01087. To investigate the function of LINC01087, gene ontology (GO) annotation and Kyoto Encyclopedia of Gene and Genomes (KEGG) enrichment analyses were performed. Furthermore, interactions between LINC01087 and both miRNA and mRNA were studied by means of bioinformatics tools. (3) Results: LINC01087 was significantly deregulated in 7 out of 30 cancers, showing a predominant upregulation. Notably, it was overexpressed in breast (BC), esophageal (ESCA), and ovarian (OV) cancers, as well as lung squamous cell carcinoma (LUSC), stomach adenocarcinoma (STAD), and uterine carcinosarcoma (UCS). By contrast, LINC01087 displayed downregulation in testicular germ cell tumors (TGCT). ROC curve analyses identified LINC01087 as a potential diagnostic indicator in BC, ESCA, OV, STAD, and TGCT. Moreover, high and low expression of LINC01087 predicted a favorable prognosis in BC and papillary cell carcinoma, respectively. In silico analyses indicated that deregulation of LINC01087 in cancer was associated with a modulation of genes related to ion channel, transporter, and peptide receptor activity. (4) Conclusions: the quantification of an altered abundance of LINC01087 in tissue specimens might be clinically useful for the diagnosis and prognosis of some hormone-related tumors, including BC, OV, and TGCT, as well as other cancer types such as ESCA and STAD. Moreover, our study revealed the potential of LINC01087 (and perhaps other lncRNAs) to regulate neuroactive molecules in cancer. 10.3390/cancers14235980
The PSMP-CCR2 interactions trigger monocyte/macrophage-dependent colitis. Pei Xiaolei,Zheng Danfeng,She Shaoping,Ma Jing,Guo Changyuan,Mo Xiaoning,Zhang Yingmei,Song Quansheng,Zhang Yu,Ma Dalong,Wang Ying Scientific reports Monocytes/macrophages have been found to be an important component of colitis. However, the key chemokine that initiates the CCR2 monocytes migration from circulation to colitis tissue remains to be undiscovered. PC3-secreted microprotein (PSMP) is a novel chemokine whose receptor is CCR2. The physiological and pathological functions of PSMP have not yet been reported. In this study, PSMP was found to be expressed in colitis and colonic tumor tissues from patients and significantly up-regulated in mouse DSS-induced colitis tissues. PSMP overexpression in the colon aggravated the DSS-induced colitis and the anti-PSMP neutralizing antibody mollified the colitis by reducing macrophage infiltration and inhibiting the expression of IL-6, TNF-α and CCL2. Furthermore, we demonstrated that lipopolysaccharide and muramyl dipeptide induced PSMP expression in the colonic epithelial cells. PSMP was up-regulated in the initial stage prior to IL-6, TNF-α and CCL2 up-regulated expression in DSS colitis and promoted the M1 macrophages to produce CCL2. PSMP chemo-attracted Ly6C monocytes in a CCR2 dependent manner via in situ chemotaxis and adoptive transfer assays. Our data identify PSMP as a key molecule in ulcerative colitis, which provides a novel mechanism of monocyte/macrophage migration that affects gut innate immunity and makes PSMP a potential target for controlling colitis. 10.1038/s41598-017-05255-7
A small peptide inhibits siRNA amplification in plants by mediating autophagic degradation of SGS3/RDR6 bodies. The EMBO journal Selective autophagy mediates specific degradation of unwanted cytoplasmic components to maintain cellular homeostasis. The suppressor of gene silencing 3 (SGS3) and RNA-dependent RNA polymerase 6 (RDR6)-formed bodies (SGS3/RDR6 bodies) are essential for siRNA amplification in planta. However, whether autophagy receptors regulate selective turnover of SGS3/RDR6 bodies is unknown. By analyzing the transcriptomic response to virus infection in Arabidopsis, we identified a virus-induced small peptide 1 (VISP1) composed of 71 amino acids, which harbor a ubiquitin-interacting motif that mediates interaction with autophagy-related protein 8. Overexpression of VISP1 induced selective autophagy and compromised antiviral immunity by inhibiting SGS3/RDR6-dependent viral siRNA amplification, whereas visp1 mutants exhibited opposite effects. Biochemistry assays demonstrate that VISP1 interacted with SGS3 and mediated autophagic degradation of SGS3/RDR6 bodies. Further analyses revealed that overexpression of VISP1, mimicking the sgs3 mutant, impaired biogenesis of endogenous trans-acting siRNAs and up-regulated their targets. Collectively, we propose that VISP1 is a small peptide receptor functioning in the crosstalk between selective autophagy and RNA silencing. 10.15252/embj.2021108050
Nonribosomal Peptide Extension by a Peptide Amino-Acyl tRNA Ligase. Zhang Zhengan,van der Donk Wilfred A Journal of the American Chemical Society The catalytic use of a small peptide scaffold for the biosynthesis of amino acid-derived natural products is a recently discovered new biosynthetic strategy. During this process, a peptide-amino acyl tRNA ligase (PEARL) adds amino acids to the C-terminus of a small peptide scaffold in an ATP- and tRNA-dependent process. The mechanism of this unusual transformation is currently not known. In this study, we present a detailed biochemical and mechanistic study of TglB (UniProtKB-F3HQJ1), a PEARL that catalyzes the addition of Cys to the C-terminus of the peptide TglA in the biosynthesis of 3-thiaglutamate in the plant pathogen . TglB recognizes several important residues close to the C-terminus of TglA to perform its activity and is tolerant with respect to the last amino acid of its substrate peptide. The enzyme recognizes the acceptor stem of tRNA, as micro- and minihelices, truncated versions of full-length tRNA that contain the acceptor stem, were also accepted. Mutagenesis of conserved residues in TglB identified several key residues for catalysis and did not support the possibility of TglB adopting various ping-pong mechanisms to catalyze the amino acid addition reaction. Using isotopic labeling studies, we demonstrate that ATP is used to directly phosphorylate the C-terminal carboxylate of TglA. Collectively, the data support a general mechanism for the amino acid addition reaction catalyzed by this class of enzyme. 10.1021/jacs.9b07111
Integrated analyses of lncRNAs microarray profiles and mRNA-lncRNA coexpression in smooth muscle cells under hypoxic and normoxic conditions. Bioscience reports Hypoxia may cause abnormal proliferation and migration of the vascular smooth muscle cells (VSMCs) from the media to the intima. This contributes to vessel narrowing and accelerates the process of atherosclerosis. The association of the aberrant expression of long noncoding RNAs (lncRNAs) with the development and progression of atherosclerosis is well known; however, it is not well investigated in hypoxic VSMCs. Using a microarray approach, we identified 1056 and 2804 differentially expressed lncRNAs and mRNAs, respectively, in hypoxic and normoxic mouse aorta smooth muscle (MOVAS) cells. Of them, we randomly chose several lncRNAs and validated the microarray data using the quantitative PCR (qPCR) assay. Advanced bioinformatics analyses indicated that the up-regulated mRNAs were mainly involved in inflammatory responses, lipid metabolism, clearance of amyloid-β peptide, citrate cycle (TCA cycle), TGF-β signaling, and chemokine signaling. The down-regulated mRNAs were mainly involved in the apoptosis pathway, glycerolipid metabolism, Wnt signaling pathway, and MAPK signaling pathway. The constructed coexpression network indicated interactions between 87 lncRNAs and ten mRNAs. In addition, we demonstrated that the silence of lncRNA NONMMUT002434 expression could abrogate the migration and proliferation of smooth muscle cells dramatically. Our data provide comprehensive evidence on the differential expression of lncRNAs and mRNAs in hypoxic MOVAS cells, which may be valuable biomarkers for atherosclerotic diseases, and thereby facilitating diagnosis of atherosclerosis. 10.1042/BSR20181783
Insight Into Pituitary lncRNA and mRNA at Two Estrous Stages in Small Tail Han Sheep With Different Genotypes. Frontiers in endocrinology The pituitary is a remarkably dynamic organ with roles in hormone (FSH and LH) synthesis and secretion. In animals with the (fecundity Booroola) mutation, the pituitary experiences hormone fluctuations during the follicular-luteal transition, which is implicated in the expression and regulation of many genes and regulators. Long non-coding RNAs (lncRNAs) are a novel type of regulatory factors for the reproductive process. Nevertheless, the expression patterns of lncRNAs and their roles in mediated follicular development and ovulation remain obscure. Thus, we profiled the pituitary transcriptome during the follicular (F, 45 h after evacuation vaginal sponges) and luteal (L, 216 h after evacuation vaginal sponges) phases in -mutant homozygous (BB) and wild-type (WW) Small Tail Han sheep. We identified 78 differentially expressed genes (DEGs) and 41 differentially expressed lncRNAs (DELs) between BB_F and BB_L, 32 DEGs and 26 DELs between BB_F and WW_F, 16 DEGs and 29 DELs between BB_L and WW_L, and 50 DEGs and 18 DELs between WW_F and WW_L. The results of real-time quantitative PCR (RT-qPCR) correlated well with the transcriptome data. In both the follicular and luteal phases, DEGs (, glutamate ionotropic receptor delta type subunit 2; , ST14 transmembrane serine protease matriptase) were enriched in hormone synthesis, secretion, and action. MSTRG.47470 and MSTRG.101530 were the -regulated elements of (inhibitor of DNA binding 3, HLH protein) and the DEG (inhibitor of DNA binding 3, HLH protein), and (eukaryotic translation elongation factor 2), respectively; these factors might be involved in melatonin and peptide hormone secretion. In the -mediated follicular phase, MSTRG.125392 targeted seizure-related 6 homolog like (), and MSTRG.125394 and MSTRG.83276 targeted the DEG (potassium voltage-gated channel subfamily Q member 3) in , while MSTRG.55861 targeted (FKBP prolyl isomerase 4) in . In the -mediated luteal phase, LOC105613905, MSTRG.81536, and MSTRG.150434 modulated , , , respectively, in . We postulated that the mutation in pituitary tissue elevated the expression of certain genes associated with pituitary development and hormone secretion. Furthermore, this study provides new insights into how the pituitary regulates follicular development and ovulation, illustrated by the effect of the mutation. 10.3389/fendo.2021.789564
Dynamics at a Peptide-TiO Anatase (101) Interface. Polimeni Marco,Petridis Loukas,Smith Jeremy C,Arcangeli Caterina The journal of physical chemistry. B The interface between biological matter and inorganic materials is a widely investigated research topic due to possible applications in biomedicine and nanotechnology. In this context, the molecular level adsorption mechanism that drives specific recognition between small peptide sequences and inorganic surfaces represents an important topic likely to provide much information useful for designing bioderived materials. Here, we investigate the dynamics at the interface between a Ti-binding peptide sequence (AMRKLPDAPGMHC) and a TiO anatase surface by using molecular dynamics (MD) simulations. In the simulations the adsorption mechanism is characterized by diffusion of the peptide from the bulk water phase toward the TiO surface, followed by the anchoring of the peptide to the surface. The anchoring is mediated by the interfacial water layers by means of the charged groups of the side chains of the peptide. The peptide samples anchored and dissociated states from the surface and its conformation is not affected by the surface when anchored. 10.1021/acs.jpcb.7b04707
A novel, small peptide with activity against human pancreatic cancer. Kozlowski Michael R,Kozlowski Roni E American journal of cancer research KTH-222 is a novel, 8-amino acid length peptide. It is derived from a motif identified in a group of peptides that are related to atrial natriuretic peptide and that are able to inhibit cancer cell growth. We report here that KTH-222 inhibits the attachment, proliferation, and development of an invasive morphology in cultured human pancreatic tumor cells (MIA PaCa-2 and HPAC). At a biochemical level, it inhibits tubulin polymerization which may underlie these cellular effects. We further report that KTH-222 reduces the rate of tumor growth and prolongs survival in mice implanted with MIA PaCa-2 cells. In this model system, KTH-222 is more effective than gemcitabine, a drug commonly used in the treatment of pancreatic cancer. Furthermore, KTH-222 does not decrease the rate of weight gain in the treated mice, suggesting the absence of gross toxicity. These activities of KTH-222 suggest that it may be useful in the treatment of pancreatic cancer.
What Can Ribo-Seq, Immunopeptidomics, and Proteomics Tell Us About the Noncanonical Proteome? Molecular & cellular proteomics : MCP Ribosome profiling (Ribo-Seq) has proven transformative for our understanding of the human genome and proteome by illuminating thousands of noncanonical sites of ribosome translation outside the currently annotated coding sequences (CDSs). A conservative estimate suggests that at least 7000 noncanonical ORFs are translated, which, at first glance, has the potential to expand the number of human protein CDSs by 30%, from ∼19,500 annotated CDSs to over 26,000 annotated CDSs. Yet, additional scrutiny of these ORFs has raised numerous questions about what fraction of them truly produce a protein product and what fraction of those can be understood as proteins according to conventional understanding of the term. Adding further complication is the fact that published estimates of noncanonical ORFs vary widely by around 30-fold, from several thousand to several hundred thousand. The summation of this research has left the genomics and proteomics communities both excited by the prospect of new coding regions in the human genome but searching for guidance on how to proceed. Here, we discuss the current state of noncanonical ORF research, databases, and interpretation, focusing on how to assess whether a given ORF can be said to be "protein coding." 10.1016/j.mcpro.2023.100631
A small peptide antagonist of the Fas receptor inhibits neuroinflammation and prevents axon degeneration and retinal ganglion cell death in an inducible mouse model of glaucoma. Journal of neuroinflammation BACKGROUND:Glaucoma is a complex, multifactorial disease where apoptosis, microglia activation, and inflammation have been linked to the death of retinal ganglion cells (RGCs) and axon degeneration. We demonstrated previously that FasL-Fas signaling was required for axon degeneration and death of RGCs in chronic and inducible mouse models of glaucoma and that Fas activation triggered RGC apoptosis, glial activation, and inflammation. Here, we investigated whether targeting the Fas receptor with a small peptide antagonist, ONL1204, has anti-inflammatory and neuroprotective effects in a microbead-induced mouse model of glaucoma. METHODS:Intracameral injection of microbeads was used to elevate intraocular pressure (IOP) in Fas-deficient (Fas) mice and WT C57BL/6J mice that received an intravitreal injection of the Fas inhibitor, ONL1204 (2 μg/1 μl) (or vehicle only), on day 0 or day 7 after microbead injection. The IOP was monitored by rebound tonometry, and at 28 days post-microbead injection, Brn3a-stained RGCs and paraphenylenediamine (PPD)-stained axons were analyzed. The effects of ONL1204 on retinal microglia activation and the expression of inflammatory genes were analyzed by immunostaining of retinal flatmounts and quantitative PCR (qPCR). RESULTS:Rebound tonometry showed equivalent elevation of IOP in all groups of microbead-injected mice. At 28 days post-microbead injection, the RGC and axon counts from microbead-injected Fas mice were equivalent to saline-injected (no IOP elevation) controls. Treatment with ONL1204 also significantly reduced RGC death and loss of axons in microbead-injected WT mice when compared to vehicle-treated controls, even when administered after IOP elevation. Confocal analysis of Iba1-stained retinal flatmounts and qPCR demonstrated that ONL1204 also abrogated microglia activation and inhibited the induction of multiple genes implicated in glaucoma, including cytokines and chemokines (GFAP, Caspase-8, TNFα, IL-1β, IL-6, IL-18, MIP-1α, MIP-1β, MIP-2, MCPI, and IP10), components of the complement cascade (C3, C1Q), Toll-like receptor pathway (TLR4), and inflammasome pathway (NLRP3). CONCLUSIONS:These results serve as proof-of-principal that the small peptide inhibitor of the Fas receptor, ONL1204, can provide robust neuroprotection in an inducible mouse model of glaucoma, even when administered after IOP elevation. Moreover, Fas signaling contributes to the pathogenesis of glaucoma through activation of both apoptotic and inflammatory pathways. 10.1186/s12974-019-1576-3
Long noncoding RNAs expression profile and functional networks in rheumatoid arthritis. Xu Donghua,Jiang Ye,Yang Lu,Hou Xixing,Wang Jihong,Gu Weijun,Wang Xiaodong,Liu Lanyu,Zhang Juan,Lu Hongying Oncotarget The modifying effects of long noncoding RNAs (lncRNAs) in rheumatoid arthritis (RA) recently have drawn much attention; however, the underlying mechanisms remain largely unknown. Herein, we aim to investigate the expression profile of lncRNAs in RA and identify promising targets for RA diagnosis and treatment. Microarray screening and real-time PCR of lncRNAs were performed by use of serum samples from 3 RA patients and 3 healthy controls. Significantly differentially expressed lncRNAs were verified in serum samples from 43 RA patients and 40 healthy controls by real-time PCR. We found that there were 73 up-regulated and 61 down-regulated lncRNAs as well as 128 up-regulated and 37 down-regulated mRNAs in serum samples of RA patients. Validation in RA clinical samples indicated 5 of these lncRNAs were significantly up-regulated including RNA143598, RNA143596, HIX0032090, IGHCgamma1, and XLOC_002730. Significant association was observed between these lncRNAs and the disease course, erythrocyte sedimentation rate (ESR), rheumatoid factor (RF) as well as anti-cyclic citrullinated peptide (anti-CCP) antibody. Additionally, 55 of the differentially expressed mRNAs were associated with 41 lncRNAs and were involved in signaling pathways of toll like receptors (TLRs), nuclear factor-kappa B (NF-κB), and cytokine, especially the IRF3/IRF7 mediated signaling transduction. Our study firstly shows the specific profile of lncRNAs in the serum of RA patients and potential signaling pathways involved in RA pathogenesis, which may provide novel targets for the diagnosis and treatment of patients with RA. 10.18632/oncotarget.20036
Solid-state fermentation with RT-3 enhanced the nutritional properties of soybeans. Frontiers in nutrition Fermented soybean products are favorite foods worldwide because of their nutritional value and health effects. In this study, solid-state fermentation (SSF) of soybeans with RT-3 was performed to investigate its nutraceutical potential. A rich enzyme system was released during SSF. Proteins were effectively transformed into small peptides and amino acids. The small peptide content increased by 13.64 times after SSF for 60 h. The antioxidant activity of soybeans was enhanced due to the release of phenolic compounds. The soluble phenolic content increased from 2.55 to 9.28 gallic acid equivalent (GAE) mg/g after SSF for 60 h and exhibited high correlations with microbial enzyme activities during SSF. The potential metabolic pathways being triggered during SSF indicated that the improved nutritional composition of soybean attributed to the biochemical reactions catalyzed by microbial enzymes. These findings demonstrated that SSF could evidently improve the nutritional value and prebiotic potential of soybeans. 10.3389/fnut.2022.972860
The cancer-associated microprotein CASIMO1 controls cell proliferation and interacts with squalene epoxidase modulating lipid droplet formation. Polycarpou-Schwarz Maria,Groß Matthias,Mestdagh Pieter,Schott Johanna,Grund Stefanie E,Hildenbrand Catherina,Rom Joachim,Aulmann Sebastian,Sinn Hans-Peter,Vandesompele Jo,Diederichs Sven Oncogene Breast cancer is a leading cause of cancer-related death in women. Small open reading frame (sORF)-encoded proteins or microproteins constitute a new class of molecules often transcribed from presumed long non-coding RNA transcripts (lncRNAs). The translation of some of these sORFs has been confirmed, but their cellular function and importance remains largely unknown. Here, we report the identification and characterization of a novel microprotein of 10 kDa, which we named Cancer-Associated Small Integral Membrane Open reading frame 1 (CASIMO1). CASIMO1 RNA is overexpressed predominantly in hormone receptor-positive breast tumors. Its knockdown leads to decreased proliferation in multiple breast cancer cell lines. Its loss disturbs the organization of the actin cytoskeleton, leads to inhibition of cell motility, and causes a G/G cell cycle arrest. The proliferation phenotype upon overexpression is observed only with CASIMO1 protein expression, but not with a non-translatable mutant attributing the effects to the sORF-derived protein rather than a lncRNA function. CASIMO1 microprotein interacts with squalene epoxidase (SQLE), a key enzyme in cholesterol synthesis and a known oncogene in breast cancer. Overexpression of CASIMO1 leads to SQLE protein accumulation without affecting its RNA levels and increased lipid droplet clustering, while knockdown of CASIMO1 decreased SQLE protein abundance and ERK phosphorylation downstream of SQLE. Importantly, SQLE knockdown mimicked the CASIMO1 knockdown phenotype and in turn SQLE overexpression fully rescued the effect of CASIMO1 knockdown. These findings establish CASIMO1 as the first functional microprotein that plays a role in carcinogenesis and is implicated in the cell lipid homeostasis. 10.1038/s41388-018-0281-5
Identification of a hippocampal lncRNA-regulating network in cognitive dysfunction caused by chronic cerebral hypoperfusion. Aging Cognitive dysfunction caused by chronic cerebral hypoperfusion is a common underlying cause of many cognition-related neurodegenerative diseases. The mechanisms of cognitive dysfunction caused by CCH are not clear. Long non-coding RNA is involved in synaptic plasticity and cognitive function, but whether lncRNA is involved in cognitive dysfunction caused by CCH has not yet been reported. In the present study, we identified the altered lncRNAs and mRNAs by deep RNA sequencing. A total of 128 mRNAs and 91 lncRNAs were up-regulated, and 108 mRNAs and 98 lncRNAs were down-regulated. Real-time reverse transcription-polymerase chain reaction verified the reliability of the lncRNA and mRNA sequencing. Gene Ontology and KEGG pathway analyses showed that differentially-expressed mRNAs were related to peptide antigen binding, the extracellular space, the monocarboxylic acid transport, and tryptophan metabolism. The co-expression analysis showed that 161 differentially expressed lncRNAs were correlated with DE mRNAs. By predicting the miRNA in which both DE lncRNAs and DE mRNAs bind together, we constructed a competitive endogenous RNA network. In this lncRNAs-miRNAs-mRNAs network, 559 lncRNA-miRNA-mRNA targeted pairs were identified, including 83 lncRNAs, 67 miRNAs, and 108 mRNAs. Through GO and KEGG pathway analysis, we further analyzed and predicted the regulatory function and potential mechanism of ceRNA network regulation. Our results are helpful for understanding the pathogenesis of cognitive dysfunction caused by CCH and provide direction for further research. 10.18632/aging.103901
A selective autophagy receptor VISP1 induces symptom recovery by targeting viral silencing suppressors. Nature communications Selective autophagy is a double-edged sword in antiviral immunity and regulated by various autophagy receptors. However, it remains unclear how to balance the opposite roles by one autophagy receptor. We previously identified a virus-induced small peptide called VISP1 as a selective autophagy receptor that facilitates virus infections by targeting components of antiviral RNA silencing. However, we show here that VISP1 can also inhibit virus infections by mediating autophagic degradation of viral suppressors of RNA silencing (VSRs). VISP1 targets the cucumber mosaic virus (CMV) 2b protein for degradation and attenuates its suppression activity on RNA silencing. Knockout and overexpression of VISP1 exhibit compromised and enhanced resistance against late infection of CMV, respectively. Consequently, VISP1 induces symptom recovery from CMV infection by triggering 2b turnover. VISP1 also targets the C2/AC2 VSRs of two geminiviruses and enhances antiviral immunity. Together, VISP1 induces symptom recovery from severe infections of plant viruses through controlling VSR accumulation. 10.1038/s41467-023-39426-0
Development of a Potent Antimicrobial Peptide With Photodynamic Activity. Zhang Di,Chen Jingyi,Jing Qian,Chen Zheng,Ullah Azeem,Jiang Longguang,Zheng Ke,Yuan Cai,Huang Mingdong Frontiers in microbiology The emergence of antibiotic-resistant bacteria poses a serious challenge to medical practice worldwide. A small peptide with sequence RWRWRW was previously identified as a core antimicrobial peptide with limited antimicrobial spectrum to bacteria, especially Gram-positive bacteria. By conjugating this peptide and its analogs with lipophilic phthalocyanine (Pc), we identified a new antibiotic peptide [PcGK(RW)]. The peptide demonstrates increased antimicrobial effect to both Gram-positive and Gram-negative . In addition, Pc also provides added and potent antimicrobial effect upon red light illumination. The inhibitory efficacy of PcGK(RW) was increased by ~140-fold to nanomolar range upon illumination. Moreover, PcGK(RW) was safe for mammalian cell and promoted wound healing in the mouse infection model. Our work provides a new direction to optimize antimicrobial peptides to enhance antimicrobial efficacy. 10.3389/fmicb.2021.624465
Oncopeptide MBOP Encoded by Promotes Colorectal Cancer through MAPK Signaling Pathway. Cancers Colorectal cancer (CRC) ranks third in incidence rate and second in mortality rate of malignancy worldwide, and the diagnosis and therapeutics of it remain to be further studied. With the emergence of noncoding RNAs (ncRNAs) and potential peptides derived from ncRNAs across various biological processes, we here aimed to identify a ncRNA-derived peptide possible for revealing the oncogenesis of CRC. Through combined predictive analysis of the coding potential of a batch of long noncoding RNAs (lncRNAs), the existence of an 85 amino-acid-peptide, named MEK1-binding oncopeptide (MBOP) and encoded from was confirmed. Mass spectrometry and Western blot assays indicated the overexpression of MBOP in CRC tissues and cell lines compared to adjacent noncancerous tissues and the normal colonic epithelial cell line. In vivo and in vitro migration and proliferation assays defined MBOP as an oncogenic peptide. Immunoprecipitation trials showed that MEK1 was the key interacting protein of MBOP, and MBOP promoted the MEK1/pERK/MMP2/MMP9 axis in CRC. Two E3-ligase enzymes MAEA and RMND5A mediated the ubiquitin-protease-system-related degradation of MBOP. This study indicates that MBOP might be a candidate prognostic indicator and a potential target for clinical therapy of CRC. 10.3390/cancers14092338
Small protein plays with big networks. Trends in genetics : TIG Thousands of small proteins, called microproteins, are encoded in small open reading frames (smORFs) throughout the genome. Despite assumptions that these proteins would be too small to properly fold and function, a recent study by Chen et al. identifies the surprisingly complex roles of one such microprotein. 10.1016/j.tig.2023.10.008
Comprehensive analysis of LncRNAs expression profiles in an in vitro model of steatosis treated with Exendin-4. Errafii Khaoula,Al-Akl Neyla S,Khalifa Olfa,Arredouani Abdelilah Journal of translational medicine BACKGROUND AND AIMS:The hallmark of non-alcoholic fatty liver disease (NAFLD) is the excessive hepatic lipid accumulation. Currently, no pharmacotherapy exists for NAFLD. However, the glucagon-like peptide-1 receptor agonists have recently emerged as potential therapeutics. Here, we sought to identify the long non-coding RNAs (LncRNAs) associated with the steatosis improvement induced by the GLP-1R agonist Exendin-4 (Ex-4) in vitro. METHODS:Steatosis was induced in HepG2 cells with oleic acid. The transcriptomic profiling was performed using total RNA extracted from untreated, steatotic, and Ex-4-treated steatotic cells. We validated a subset of differentially expressed LncRNAs with qRT-PCR and identified the most significantly enriched cellular functions associated with the relevant LncRNAs. RESULTS:We confirm that Ex-4 improves steatosis in HepG2 cells. We found 379 and 180 differentially expressed LncRNAs between untreated and steatotic cells and between steatotic and Ex-4-treated steatotic cells, respectively. Interestingly, 22 upregulated LncRNAs in steatotic cells became downregulated with Ex-4 exposure, while 50 downregulated LncRNAs in steatotic cells became upregulated in the presence of Ex-4. Although some LncRNAs, such as MALAT1, H19, and NEAT1, were previously associated with NAFLD, the association of others with steatosis and the positive effect of Ex-4 is being reported for the first time. Functional enrichment analysis identified many critical pathways, including fatty acid and pyruvate metabolism, and insulin, PPAR, Wnt, TGF-β, mTOR, VEGF, NOD-like, and Toll-like receptors signaling pathways. CONCLUSION:Our results suggest that LncRNAs may play essential roles in the mechanisms underlying steatosis improvement in response to GLP-1R agonists and warrant further functional studies. 10.1186/s12967-021-02885-4
Peptide Linked Diacetylene Amphiphiles for Detection of Epitope Specific Antibodies. Chemosensors (Basel, Switzerland) Antibodies produced in response to adaptive immunity provide a receptor with multiple sites for binding to a distinct epitope of an antigen. Determining antibody levels to specific antigens has important clinical applications in assessing immune status or deficiency, monitoring infectious or autoimmune diseases, and diagnosing allergies. Leveraging that a specific antibody will bind to a distinct small peptide epitope without requiring the entire antigen to be present, we demonstrate in this work a proof-of-concept assay to detect the presence of an antibody by using peptide epitopes linked to an amphiphile to generate a vesicle-based sensing system. By affording multiple copies of the epitope site on the vesicle, we revealed that the vesicles visibly aggregate in response to an antibody specific for that epitope due to multivalent binding provided by the antibody. We also uncovered the role of peptide surface density in providing accessible epitopes on the vesicles for antibody binding. In summary, using a peptide derived from the coat protein of human influenza virus directly linked to a diacetylene-containing amphiphile afforded peptide-laden vesicles that proved capable of detecting the presence of antibodies specific for human influenza hemagglutinin. 10.3390/chemosensors10020062
Expanded Sequence Space of Radical S-Adenosylmethionine-Dependent Enzymes Involved in Post-translational Macrocyclization. Angewandte Chemie (International ed. in English) Ribosomally synthesized and post-translationally modified peptides (RiPPs) represent one of the largest but primarily underexplored natural product families in bacteria. The genetically encoded nature of RiPPs simplifies the prediction and prioritization of their biosynthetic gene clusters (BGCs). We report a small peptide and enzyme co-occurrence analysis workflow (SPECO), which allowed us to identify 32 220 prospective rSAM-catalyzed RiPP BGCs from 161 954 bacterial genomes and prioritize 25 families with new biosynthetic architectures or precursor patterns. We characterized three new enzymes that respectively catalyze cysteine-glycine (BlaB), histidine-aliphatic side chain (ScaB), and tyrosine/histidine-arginine (VguB) cross-links. The cyclophane-forming enzyme ScaB exhibits broad substrate selectivity, allowing it to catalyze diverse triceptide formation. These results demonstrate the strength of the SPECO workflow in discovering new enzymes for peptide macrocyclization. 10.1002/anie.202212447
Leptin: an entry point for the treatment of peripheral tissue fibrosis and related diseases. Liu Yuexia,Li Yizhou,Liang Juntong,Sun Zhuwen,Wu Qiong,Liu Yongnian,Sun Chao International immunopharmacology Leptin is a small peptide mainly secreted by adipocyte, which acts on the central nervous system of the hypothalamus to regulate the body's energy balance by inhibiting food intake, it also can directly act on specific cells through leptin receptors (for example, ObRa, which exists in the blood-brain barrier or kidneys), thereby affect cell metabolism. Excessive deposition of extracellular matrix (ECM) causes damage to normal tissues or destruction of organ structure, which will eventually lead to tissue or organ fibrosis. The sustainable development of fibrosis can lead to structural damage and functional decline of organs, and even exhaustion, which seriously threatens human health and life. In recent years, studies have found that leptin directly alleviates the fibrosis process of various tissues and organs in mammals. Therefore, we speculate that leptin may become a significant treatment for fibrosis of various tissues and organs in the future. So, the main purpose of this review is to explore the specific mechanism of leptin in the process of fibrosis in multiple tissues and organs, and to provide a theoretical basis for the treatment of various tissues and organs fibrosis and related diseases caused by it, which is of great significance in the future. 10.1016/j.intimp.2022.108608
Downregulation of lncRNA MALAT1 Inhibits Angiotensin II-induced Hypertrophic Effects of Cardiomyocytes by Regulating SIRT4 via miR-93-5p. International heart journal Cardiac hypertrophy is a leading risk for heart failure and sudden death. Long non-coding RNAs (lncRNAs) have been implicated in a variety of human diseases, including cardiac hypertrophy. We aimed to investigate the potential role and functional mechanism of lncRNA metastasis-associated in lung adenocarcinoma transcript 1 (MALAT1) in cardiac hypertrophy. C57BL/6 mice underwent transverse aortic constriction (TAC) to induce cardiac hypertrophy in vivo. The expression of MALAT1, miR-93-5p, and sirtuin 4 (SIRT4) mRNA was detected using a quantitative real-time polymerase chain reaction. The protein levels of cardiac hypertrophy-related markers, including atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP) and β-myosin heavy chain (β-MHC), and SIRT4 were measured via western blotting. The putative interaction between miR-93-5p and MALAT1 or SIRT4 was verified using a dual-luciferase reporter assay, RNA immunoprecipitation assay, or pull-down assay. Consequently, the expression of MALAT1 and SIRT4 was increased in TAC-treated mouse heart and angiotensin II (Ang-II)-induced cardiomyocytes, whereas the expression of miR-93-5p was decreased. Ang-II promoted the expression of ANP, BNP, and β-MHC and the surface area of cardiomyocytes, whereas MALAT1 downregulation impaired their expression and cell area. MiR-93-5p was a target of MALAT1, and its inhibition reversed the effects of MALAT1 downregulation. More importantly, MALAT1 modulated SIRT4 expression by degrading miR-93-5p. The expression of ANP, BNP, and β-MHC suppressed by miR-93-5p restoration was recovered by SIRT4 promotion. Overall, MALAT1 knockdown ameliorated cardiac hypertrophy partly by regulating the miR-93-5p/SIRT4 network, indicating that MALAT1 was a substantial indicator of cardiac hypertrophy. 10.1536/ihj.21-332
LINC01420 RNA structure and influence on cell physiology. Konina Daria O,Filatova Alexandra Yu,Skoblov Mikhail Yu BMC genomics BACKGROUND:It was shown that the major part of human genome is transcribed and produces a large number of long noncoding RNAs (lncRNAs). Today there are many evidences that lncRNAs play important role in the regulation of gene expression during different cellular processes. Moreover, lncRNAs are involved in the development of various human diseases. However, the function of the major part of annotated transcripts is currently unknown, whereas different lncRNAs annotations tend to have low overlap. Recent studies revealed that some lncRNAs have small open reading frames (smORFs), that produce the functional microproteins. However, the question whether the function of such genes is determined by microprotein or RNA itself or both remains open. Thus, the study of new lncRNA genes is important to understanding the functional role of such a heterogeneous class of genes. RESULTS:In the present study, we used reverse transcription PCR and rapid amplification of cDNA ends (RACE) analysis to determine the structure of the LINC01420 transcript. We revealed that LINC01420 has two isoforms that differ in length of the last exon and are localized predominantly in the cytoplasm. We showed that expression of the short isoform is much higher than the long. Besides, MTT and wound-healing assays revealed that LINC01420 inhibited cell migration in human melanoma cell line A375, but does not influence on cell viability. CONCLUSION:During our work, D'Lima et al. found smORF in the first exon of the LINC01420 gene. This smORF produces functional microprotein named non-annotated P-body dissociating polypeptide (NoBody). However, our results provide new facts about LINC01420 transcript and its function. 10.1186/s12864-019-5538-z
The Amyloid Cascade Hypothesis in Alzheimer's Disease: It's Time to Change Our Mind. Current neuropharmacology Since its discovery in 1984, the beta amyloid peptide has treaded the boards of neurosciences as the star molecule in Alzheimer's disease pathogenesis. In the last decade, however, this vision has been challenged by evidence-based medicine showing the almost complete failure of clinical trials that experimented anti-amyloid therapies with great hopes. Moreover, data have accumulated which clearly indicate that this small peptide plays a key role in the physiological processes of memory formation. In the present review, we will discuss the different aspects of the amyloid cascade hypothesis, highlighting its pros and cons, and we will analyse the results of the therapeutic approaches attempted to date that should change the direction of Alzheimer's disease research in the future. 10.2174/1570159X15666170116143743
Mutant p53 in Cancer Progression and Targeted Therapies. Zhu Gaoyang,Pan Chaoyun,Bei Jin-Xin,Li Bo,Liang Chen,Xu Yang,Fu Xuemei Frontiers in oncology is the most frequently mutated tumor suppressor gene in human cancer. The majority of mutations of p53 are missense mutations, leading to the expression of the full length p53 mutant proteins. Mutant p53 (Mutp53) proteins not only lose wild-type p53-dependent tumor suppressive functions, but also frequently acquire oncogenic gain-of-functions (GOF) that promote tumorigenesis. In this review, we summarize the recent advances in our understanding of the oncogenic GOF of mutp53 and the potential therapies targeting mutp53 in human cancers. In particular, we discuss the promising drugs that are currently under clinical trials as well as the emerging therapeutic strategies, including CRISPR/Cas9 based genome edition of mutant allele, small peptide mediated restoration of wild-type p53 function, and immunotherapies that directly eliminate mutp53 expressing tumor cells. 10.3389/fonc.2020.595187
Short open reading frames (sORFs) and microproteins: an update on their identification and validation measures. Journal of biomedical science A short open reading frame (sORFs) constitutes ≤ 300 bases, encoding a microprotein or sORF-encoded protein (SEP) which comprises ≤ 100 amino acids. Traditionally dismissed by genome annotation pipelines as meaningless noise, sORFs were found to possess coding potential with ribosome profiling (RIBO-Seq), which unveiled sORF-based transcripts at various genome locations. Nonetheless, the existence of corresponding microproteins that are stable and functional was little substantiated by experimental evidence initially. With recent advancements in multi-omics, the identification, validation, and functional characterisation of sORFs and microproteins have become feasible. In this review, we discuss the history and development of an emerging research field of sORFs and microproteins. In particular, we focus on an array of bioinformatics and OMICS approaches used for predicting, sequencing, validating, and characterizing these recently discovered entities. These strategies include RIBO-Seq which detects sORF transcripts via ribosome footprints, and mass spectrometry (MS)-based proteomics for sequencing the resultant microproteins. Subsequently, our discussion extends to the functional characterisation of microproteins by incorporating CRISPR/Cas9 screen and protein-protein interaction (PPI) studies. Our review discusses not only detection methodologies, but we also highlight on the challenges and potential solutions in identifying and validating sORFs and their microproteins. The novelty of this review lies within its validation for the functional role of microproteins, which could contribute towards the future landscape of microproteomics. 10.1186/s12929-022-00802-5
Classification and function of small open reading frames. Couso Juan-Pablo,Patraquim Pedro Nature reviews. Molecular cell biology Small open reading frames (smORFs) of 100 codons or fewer are usually - if arbitrarily - excluded from proteome annotations. Despite this, the genomes of many metazoans, including humans, contain millions of smORFs, some of which fulfil key physiological functions. Recently, the transcriptome of Drosophila melanogaster was shown to contain thousands of smORFs of different classes that actively undergo translation, which produces peptides of mostly unknown function. Here, we present a comprehensive analysis of smORFs in flies, mice and humans. We propose the existence of several functional classes of smORFs, ranging from inert DNA sequences to transcribed and translated cis-regulators of translation and peptides with a propensity to function as regulators of membrane-associated proteins, or as components of ancient protein complexes in the cytoplasm. We suggest that the different smORF classes could represent steps in gene, peptide and protein evolution. Our analysis introduces a distinction between different peptide-coding classes of smORFs in animal genomes, and highlights the role of model organisms for the study of small peptide biology in the context of development, physiology and human disease. 10.1038/nrm.2017.58
Microprotein Dysregulation in the Serum of Patients with Atrial Fibrillation. Journal of proteome research The incidence rate of atrial fibrillation (AF) has stayed at a high level in recent years. Despite the intensive efforts to study the pathologic changes of AF, the molecular mechanism of disease development remains unclarified. Microproteins are ribosomally translated gene products from small open reading frames (sORFs) and are found to play crucial biological functions, while remain rare attention and indistinct in AF study. In this work, we recruited 65 AF patients and 65 healthy subjects for microproteomic profiling. By differential analysis and cross-validation between independent datasets, a total of 4 microproteins were identified as significantly different, including 3 annotated ones and 1 novel one. Additionally, we established a diagnostic model with either microproteins or global proteins by machine learning methods and found the model with microproteins achieved comparable and excellent performance as that with global proteins. Our results confirmed the abnormal expression of microproteins in AF and may provide new perspectives on the mechanism study of AF. 10.1021/acs.jproteome.2c00622
Effect of replacing inorganic minerals with small peptide chelated minerals on production performance, some biochemical parameters and antioxidant status in broiler chickens. Frontiers in physiology Due to the low bio-availability of inorganic trace minerals, its application in poultry production has been causing many problems such as environment pollution and waste of resources. The current study was designed to evaluate if replacing inorganic trace minerals (ITM) with small peptide chelate trace minerals (SPM) affects production performance, some biochemical parameters and antioxidant status, tibia mineral deposition, and fecal mineral content in 817 white-feathered broilers. A total of 432 broilers (21-day-old) were randomly divided into four groups with six replicates of 18 chicks each. The four groups included inorganic trace minerals group (addition of 1,000 mg/kg ITM; common practice by commercial poultry farms), three organic trace minerals groups with supplementation of 150, 300, and 500 mg/kg SPM, respectively. The experiment lasted for 30 days. The results showed that there was no significant difference in growth performance and slaughter performance among the four groups ( > 0.05). Total cholesterol in the SPM group was significantly lower than those in the ITM groups ( < 0.01). Compared with the ITM group, the serum urea nitrogen in 150 and 300 mg/kg SPM groups decreased significantly ( < 0.01). Among all SPM treatments, 300 mg/kg SPM groups had the highest serum glutathione peroxidase (GSH-Px) activity ( < 0.01). The activity of copper and zinc superoxide dismutase (Cu/Zn SOD) of liver in ITM group was the lowest among the four groups ( < 0.01). The catalase (CAT) activity of liver in the 150 mg/kg SPM group was significantly higher than the ITM group and 300 mg/kg SPM group ( < 0.05). Compared to the ITM group, the iron content of the tibia was significantly increased in 300 mg/kg SPM group ( < 0.05) and 500 mg/kg SPM group ( < 0.01). Compared to the ITM group, dietary supplementation with SPM significantly reduced fecal content of zinc and manganese ( < 0.01). The 150 mg/kg SPM and 300 mg/kg SPM group had significantly reduced content of iron ( < 0.05). This study demonstrated that replacing inorganic minerals with low doses of SPM (300 and 500 mg/kg) did not negatively affect growth and slaughter performance, as well as the antioxidant status of broiler chickens. In addition, SPM can also promote mineral content in the tibia and reduce mineral content in the feces. 10.3389/fphys.2022.1027834
LncVar: Deciphering Genetic Variations Associated with Long Noncoding Genes. Chen Xiaowei,Hao Yajing,Cui Ya,Fan Zhen,Chen Runsheng Methods in molecular biology (Clifton, N.J.) Long noncoding RNAs (lncRNAs) are pervasively transcribed in various species and play important roles in many biological processes. The biological functions of most lncRNAs remain to be explored. Previous studies have revealed that a large amount of disease-associated variations are located in the lncRNA gene regions. To evaluate the effects of genetic variations on lncRNAs, we constructed a database of genetic variations associated with long noncoding genes, LncVar. In this chapter, we describe the process of collecting data (including lncRNAs, transcription factor binding sites and mA modification sites of lncRNAs, putatively translated open reading frames in lncRNAs) and steps of evaluating the effects of variations on the transcriptional regulation and modification of lncRNAs. 10.1007/978-1-4939-8808-2_14
Versatile Labeling and Detection of Endogenous Proteins Using Tag-Assisted Split Enzyme Complementation. ACS chemical biology Recent advances in genome engineering have expanded our capabilities to study proteins in their natural states. In particular, the ease and scalability of knocking-in small peptide tags has enabled high throughput tagging and analysis of endogenous proteins. To improve enrichment capacities and expand the functionality of knock-ins using short tags, we developed the tag-assisted split enzyme complementation (TASEC) approach, which uses two orthogonal small peptide tags and their cognate binders to conditionally drive complementation of a split enzyme upon labeled protein expression. Using this approach, we have engineered and optimized the tag-assisted split HaloTag complementation system (TA-splitHalo) and demonstrated its versatile applications in improving the efficiency of knock-in cell enrichment, detection of protein-protein interaction, and isolation of biallelic gene edited cells through multiplexing. 10.1021/acschembio.0c00925
Global analysis of ribosome-associated noncoding RNAs unveils new modes of translational regulation. Bazin Jérémie,Baerenfaller Katja,Gosai Sager J,Gregory Brian D,Crespi Martin,Bailey-Serres Julia Proceedings of the National Academy of Sciences of the United States of America Eukaryotic transcriptomes contain a major non-protein-coding component that includes precursors of small RNAs as well as long noncoding RNA (lncRNAs). Here, we utilized the mapping of ribosome footprints on RNAs to explore translational regulation of coding and noncoding RNAs in roots of shifted from replete to deficient phosphorous (Pi) nutrition. Homodirectional changes in steady-state mRNA abundance and translation were observed for all but 265 annotated protein-coding genes. Of the translationally regulated mRNAs, 30% had one or more upstream ORF (uORF) that influenced the number of ribosomes on the principal protein-coding region. Nearly one-half of the 2,382 lncRNAs detected had ribosome footprints, including 56 with significantly altered translation under Pi-limited nutrition. The prediction of translated small ORFs (sORFs) by quantitation of translation termination and peptidic analysis identified lncRNAs that produce peptides, including several deeply evolutionarily conserved and significantly Pi-regulated lncRNAs. Furthermore, we discovered that natural antisense transcripts (NATs) frequently have actively translated sORFs, including five with low-Pi up-regulation that correlated with enhanced translation of the sense protein-coding mRNA. The data also confirmed translation of miRNA target mimics and lncRNAs that produce -acting or phased small-interfering RNA (RNA/phasiRNAs). Mutational analyses of the positionally conserved sORF of linked its translation with RNA biogenesis. Altogether, this systematic analysis of ribosome-associated mRNAs and lncRNAs demonstrates that nutrient availability and translational regulation controls protein and small peptide-encoding mRNAs as well as a diverse cadre of regulatory RNAs. 10.1073/pnas.1708433114
Bombyx mori cypovirus encoded small peptide inhibits viral multiplication. Hu Xiaolong,Chen Fei,Zhu Liyuan,Yu Lei,Zhu Min,Liang Zi,Zhang Xing,Xue Renyu,Cao Guangli,Gong Chengliang Developmental and comparative immunology Bombyx mori cypovirus (BmCPV) is one of the most infectious pathogen in sericulture and a member of the family Reoviridae. It specifically infects the midgut of silkworm. The BmCPV genome consists of 10 dsRNAs segments (S1-S10), which have generally been assumed to be monocistronic. In this study, a small open reading frame encoding the peptide S5-sORF, containing 27 amino acid residues, was predicted in a region of the negative (-) strand of BmCPV segment S5. An immunofluorescence assay detected S5-sORF in the cytoplasm and nuclei of BmCPV-infected cells, and it was also detected in the virion with western blotting, suggesting that S5-sORF may be assembled into the BmCPV virion. Viral gene expression was inhibited by overexpressed S5-sORF, and viral multiplication was dose-dependently suppressed by the S5-sORF peptide. A viable recombinant virus, BmCPV-S5-sORF, in which the start codon (ATG) of S5-sORF was mutated to a stop codon (TGA), was generated with reverse genetics. The proliferation of BmCPV was increased by the abolition of S5-sORF expression. Furthermore, the RNA transcript of S5-sORF and small peptide of S5-sORF were involved in BmCPV replication. The expression of genes related to the innate immune pathways and apoptosis in the silkworm were not significantly affected by S5-sORF overexpression. Our results suggest that a viral nucleotide sequence is utilized by the host to generate an antiviral peptide, which may be a novel strategy protecting the host from viral infection. 10.1016/j.dci.2019.02.017
The microprotein Minion controls cell fusion and muscle formation. Zhang Qiao,Vashisht Ajay A,O'Rourke Jason,Corbel Stéphane Y,Moran Rita,Romero Angelica,Miraglia Loren,Zhang Jia,Durrant Eric,Schmedt Christian,Sampath Srinath C,Sampath Srihari C Nature communications Although recent evidence has pointed to the existence of small open reading frame (smORF)-encoded microproteins in mammals, their function remains to be determined. Skeletal muscle development requires fusion of mononuclear progenitors to form multinucleated myotubes, a critical but poorly understood process. Here we report the identification of Minion (microprotein inducer of fusion), a smORF encoding an essential skeletal muscle specific microprotein. Myogenic progenitors lacking Minion differentiate normally but fail to form syncytial myotubes, and Minion-deficient mice die perinatally and demonstrate a marked reduction in fused muscle fibres. The fusogenic activity of Minion is conserved in the human orthologue, and co-expression of Minion and the transmembrane protein Myomaker is sufficient to induce cellular fusion accompanied by rapid cytoskeletal rearrangement, even in non-muscle cells. These findings establish Minion as a novel microprotein required for muscle development, and define a two-component programme for the induction of mammalian cell fusion. Moreover, these data also significantly expand the known functions of smORF-encoded microproteins. 10.1038/ncomms15664
Molecular Basis of Phage Communication. Molecular cell Recently members of Bacillus phages were found to utilize a small peptide (6 aa long) to communicate with their descendants, aiding in a complex decision-making process. Proteins involved in this remarkable viral communication phenomenon were further investigated at the structural level for better understanding in this issue of Molecular Cell (Gallego del Sol et al., 2019). 10.1016/j.molcel.2019.03.015
The cardiac-enriched microprotein mitolamban regulates mitochondrial respiratory complex assembly and function in mice. Proceedings of the National Academy of Sciences of the United States of America Emerging evidence indicates that a subset of RNA molecules annotated as noncoding contain short open reading frames that code for small functional proteins called microproteins, which have largely been overlooked due to their small size. To search for cardiac-expressed microproteins, we used a comparative genomics approach and identified mitolamban (Mtlbn) as a highly conserved 47-amino acid transmembrane protein that is abundantly expressed in the heart. Mtlbn localizes specifically to the inner mitochondrial membrane where it interacts with subunits of complex III of the electron transport chain and with mitochondrial respiratory supercomplexes. Genetic deletion of Mtlbn in mice altered complex III assembly dynamics and reduced complex III activity. Unbiased metabolomic analysis of heart tissue from Mtlbn knockout mice further revealed an altered metabolite profile consistent with deficiencies in complex III activity. Cardiac-specific Mtlbn overexpression in transgenic (TG) mice induced cardiomyopathy with histological, biochemical, and ultrastructural pathologic features that contributed to premature death. Metabolomic analysis and biochemical studies indicated that hearts from Mtlbn TG mice exhibited increased oxidative stress and mitochondrial dysfunction. These findings reveal Mtlbn as a cardiac-expressed inner mitochondrial membrane microprotein that contributes to mitochondrial electron transport chain activity through direct association with complex III and the regulation of its assembly and function. 10.1073/pnas.2120476119
The Role of Ghrelin in Regulating Synaptic Function and Plasticity of Feeding-Associated Circuits. Serrenho Débora,Santos Sandra D,Carvalho Ana Luísa Frontiers in cellular neuroscience Synaptic plasticity of the neuronal circuits associated with feeding behavior is regulated by peripheral signals as a response to changes in the energy status of the body. These signals include glucose, free fatty acids, leptin and ghrelin and are released into circulation, being able to reach the brain. Ghrelin, a small peptide released from the stomach, is an orexigenic hormone produced in peripheral organs, and its action regulates food intake, body weight and glucose homeostasis. Behavioral studies show that ghrelin is implicated in the regulation of both hedonic and homeostatic feeding and of cognition. Ghrelin-induced synaptic plasticity has been described in neuronal circuits associated with these behaviors. In this review, we discuss the neuromodulatory mechanisms induced by ghrelin in regulating synaptic plasticity in three main neuronal circuits previously associated with feeding behaviors, namely hypothalamic (homeostatic feeding), ventral tegmental (hedonic and motivational feeding) and hippocampal (cognitive) circuits. Given the central role of ghrelin in regulating feeding behaviors, and the altered ghrelin levels associated with metabolic disorders such as obesity and anorexia, it is of paramount relevance to understand the effects of ghrelin on synaptic plasticity of neuronal circuits associated with feeding behaviors. 10.3389/fncel.2019.00205
LncRNA DGCR5-encoded polypeptide RIP aggravates SONFH by repressing nuclear localization of β-catenin in BMSCs. Cell reports The differentiation fate of bone marrow mesenchymal stem cells (BMSCs) affects the progression of steroid-induced osteonecrosis of the femoral head (SONFH). We find that lncRNA DGCR5 encodes a 102-amino acid polypeptide, RIP (Rac1 inactivated peptide), which promotes the adipogenic differentiation of BMSCs and aggravates the progression of SONFH. RIP, instead of lncRNA DGCR5, binds to the N-terminal motif of RAC1, and inactivates the RAC1/PAK1 cascade, resulting in decreased Ser675 phosphorylation of β-catenin. Ultimately, the nuclear localization of β-catenin decreases, and the differentiation balance of BMSCs tilts toward the adipogenesis lineage. In the femoral head of rats, overexpression of RIP causes trabecular bone disorder and adipocyte accumulation, which can be rescued by overexpressing RAC1. This finding expands the regulatory role of lncRNAs in BMSCs and suggests RIP as a potential therapeutic target. 10.1016/j.celrep.2023.112969
Long noncoding RNAs with peptide-encoding potential identified in esophageal squamous cell carcinoma: KDM4A-AS1-encoded peptide weakens cancer cell viability and migratory capacity. Molecular oncology Currently, the knowledge of long noncoding RNA (lncRNA)-encoded peptides is quite lacking in esophageal squamous cell carcinoma (ESCC). In this study, we simultaneously identified six lncRNA open reading frames (ORFs) with peptide-coding abilities including lysine-specific demethylase 4A antisense RNA 1 (KDM4A-AS1) ORF by combining weighted gene co-expression network analysis (WGCNA) for ESCC clinical samples, ribosome footprints, ORF prediction, mass spectrometry (MS) identification, and western blotting. KDM4A-AS1 ORF-encoded peptide reduced ESCC cell viability and migratory ability. Co-immunoprecipitation and MS analysis revealed that KDM4A-AS1-encoded peptide specifically bound with 103 proteins in ESCC cells, and enrichment analysis suggested that peptide-bound proteins were related to fatty acid metabolism and redox process. Cell and molecular experiments demonstrated that KDM4A-AS1-encoded peptide inhibited stearoyl-CoA desaturase and fatty acid synthase expression, increased reactive oxygen species level, and reduced mitochondrial membrane potential in ESCC cells. In summary, multiple lncRNAs with translation potential were simultaneously identified by combining multiple approaches in ESCC, providing novel identification strategies for lncRNA-encoded peptides. Moreover, lncRNA KDM4A-AS1-encoded peptide weakened ESCC cell viability and migratory capacity and functioned in fatty acid metabolism and redox process. 10.1002/1878-0261.13424
Small peptide glutathione-induced bioflocculation for enhancing the food application potential of Chlorella pyrenoidosa. Bioresource technology Existing flocculants are used to enhance the harvesting efficiency of microalgae; however, harvesting biomass containing residues is unsuitable for food applications. In this study, a small peptide-induced bioflocculation technique was developed for harvesting microalgae, and the biomass was free of impurities. After seven days of cultivation with glutathione, 72 % flocculation efficiency of Chlorella pyrenoidosa was achieved after settling for 1 h. The nutrient composition of flocs depicted a higher protein (68.94 mg/L) and lipid (48.97 mg/L) content than those of the control (65.91 and 41.44 mg/L). The amino acid profiles of flocs showed the presence of more essential amino acids than in untreated cells. More omega polyunsaturated fatty acids, such as ω-3 and ω-9, accumulate in flocs. Extracellular polymeric substances, which induced bioflocculation, appeared markedly in flocs (150.02 mg/L) compared to the control (32.30 mg/L). This study provides novel insights into the residue-free algal harvesting method and obtained nutrition-enriched biomass. 10.1016/j.biortech.2022.128138
-encoded microprotein mitoregulin regulates fatty acid metabolism at the mitochondrial outer membrane. iScience encodes a microprotein first identified as Mitoregulin (MTLN), where it was reported to localize to the inner membrane of mitochondria to regulate fatty acid oxidation and oxidative phosphorylation. These initial discoveries were followed by reports with differing findings about its molecular functions and submitochondrial localization. To clarify the apparent discrepancies, we constructed multiple orthogonal methods of determining the localization of MTLN, including split GFP-based reporters that enable efficient and reliable topology analyses for microproteins. These methods unequivocally demonstrate MTLN primarily localizes to the outer membrane of mitochondria, where it interacts with enzymes of fatty acid metabolism including CPT1B and CYB5B. Loss of MTLN causes the accumulation of very long-chain fatty acids (VLCFAs), especially docosahexaenoic acid (DHA). Intriguingly, loss of MTLN protects mice against western diet/fructose-induced insulin-resistance, suggests a protective effect of VLCFAs in this context. MTLN thus serves as an attractive target to control the catabolism of VLCFAs. 10.1016/j.isci.2023.107558
A Peptide Encoded by a Long Non-Coding RNA DLX6-AS1 Facilitates Cell Proliferation, Migration, and Invasion by Activating the wnt/β-Catenin Signaling Pathway in Non-Small-Cell Lung Cancer Cell. Critical reviews in eukaryotic gene expression Recently, accumulating study shows that some long non-coding RNAs (lncRNAs) have potential protein/peptide-coding capacities. In this study, the coding potential of lncRNA distal-less homeobox 6 antisense 1 (DLX6-AS1) was examined and the roles and downstream pathways of a DLX6-AS1-encoded peptide in non-small-cell lung cancer (NSCLC) cell development were investigated. The peptide-coding potential of lncRNA DLX6-AS1 was extrapolated based on prior ribosome footprint and ribosome sequencing data, IPX0002962000 mass spectrometry dataset, and Getorf bioinformatics analysis. The peptide-coding abilities of several DLX6-AS1 open reading frame (ORF) fragments, as well as protein levels were detected by Western blot assay. Cell proliferative, migratory, and invasive abilities were tested by CCK-8 or Transwell assays, respectively. Potential key biological processes and pathways related to DLX6-AS1 expression were identified by single-gene gene set enrichment analysis (GSEA) based on RNA-seq data of 510 lung adenocarcinoma samples in the TCGA GDC database. The results showed that an ORF of lncRNA DLX6-AS1 could encode a short peptide. The exogenous overexpression of this ORF-encoded peptide promoted NSCLC cell proliferation, migration, and invasion. GSEA analysis suggested that DLX6-AS1 might play crucial roles in cancer progression and wnt signaling pathway. Further analysis revealed that the exogenous overexpression of a DLX6-AS1-encoded peptide could exert its functions by activating the wnt/β-catenin pathway in NSCLC cells. In conclusion, the exogenous overexpression of a DLX6-AS1-encoded peptide could facilitate NSCLC cell growth by activating wnt/β-catenin pathway. 10.1615/CritRevEukaryotGeneExpr.2022043172
BONCAT-based Profiling of Nascent Small and Alternative Open Reading Frame-encoded Proteins. Bio-protocol RIBO-seq and proteogenomics have revealed that mammalian genomes harbor thousands of unannotated small and alternative open reading frames (smORFs, <100 amino acids, and alt-ORFs, >100 amino acids, respectively). Several dozen mammalian smORF-encoded proteins (SEPs) and alt-ORF-encoded proteins (alt-proteins) have been shown to play important biological roles, while the overwhelming majority of smORFs and alt-ORFs remain uncharacterized, particularly at the molecular level. Functional proteomics has the potential to reveal key properties of unannotated SEPs and alt-proteins in high throughput, and an approach to identify SEPs and alt-proteins undergoing regulated synthesis should be of broad utility. Here, we introduce a chemoproteomic pipeline based on bio-orthogonal non-canonical amino acid tagging (BONCAT) (Dieterich et al., 2006) to profile nascent SEPs and alt-proteins in human cells. This approach is able to identify cellular stress-induced and cell-cycle regulated SEPs and alt-proteins in cells. Graphical abstract Schematic overview of BONCAT-based chemoproteomic profiling of nascent, unannotated small and alternative open reading frame-encoded proteins (SEPs and alt-proteins). 10.21769/BioProtoc.4585
Discovery of low-molecular weight anti-PD-L1 peptides for cancer immunotherapy. Liu Hao,Zhao Zhen,Zhang Li,Li Yuanke,Jain Akshay,Barve Ashutosh,Jin Wei,Liu Yanli,Fetse John,Cheng Kun Journal for immunotherapy of cancer BACKGROUND:Immunotherapy using checkpoint inhibitors, especially PD-1/PD-L1 inhibitors, has now evolved into the most promising therapy for cancer patients. However, most of these inhibitors are monoclonal antibodies, and their large size may limit their tumor penetration, leading to suboptimal efficacy. As a result, there has been a growing interest in developing low-molecular-weight checkpoint inhibitors. METHODS:We developed a novel biopanning strategy to discover small peptide-based anti-PD-L1 inhibitors. The affinity and specificity of the peptides to PD-L1 were examined using various assays. Three-dimensional (3D) spheroid penetration study was performed to determine the tumor penetration capability of the peptides. Anti-tumor activity of the peptides was evaluated in mice bearing CT26 tumor cells. RESULTS:We discover several anti-PD-L1 peptide inhibitors to block PD-1/PD-L1 interaction. The peptides exhibit high affinity and specificity to human PD-L1 protein as well as PD-L1-overexpressing human cancer cells MDA-MB-231 and DU-145. Molecular docking studies indicate that the peptide CLP002 specifically binds to PD-L1 at the residues where PD-L1 interacts with PD-1. The peptide also blocks the CD80/PD-L1 interaction, which may further enhance the immune response of tumor-infiltrating T cells. Compared to antibody, the peptide CLP002 exhibits better tumor penetration in a 3D tumor spheroid model. The peptide CLP002 restores proliferation and prevents apoptosis of T cells that are co-cultured with cancer cells. The peptide CLP002 also inhibits tumor growth and increases survival of CT26 tumor-bearing mice. CONCLUSIONS:This study demonstrated the feasibility of using phage display to discover small peptide-based checkpoint inhibitors. Our results also suggested that the anti-PD-L1 peptide represents a promising low-molecular-weight checkpoint inhibitor for cancer immunotherapy. 10.1186/s40425-019-0705-y
Peptides/Proteins Encoded by Non-coding RNA: A Novel Resource Bank for Drug Targets and Biomarkers. Zhu Song,Wang Jizhong,He Yutian,Meng Nan,Yan Guang-Rong Frontiers in pharmacology Non-coding RNAs (ncRNAs) are defined as RNA molecules that do not encode proteins, but recent evidence has proven that peptides/proteins encoded by ncRNAs do indeed exist and usually contain less than 100 amino acids. These peptides/proteins play an important role in regulating tumor energy metabolism, epithelial to mesenchymal transition of cancer cells, the stability of the c-Myc oncoprotein, and the ubiquitination and degradation of proliferating cell nuclear antigen (PCNA). These peptides/proteins represent promising drug targets for fighting against tumor growth or biomarkers for predicting the prognosis of cancer patients. In this review, we summarize the characteristics of peptides/proteins that have recently been identified as putative ncRNA translation products and their outlook for small molecule peptide drugs, drug targets, and biomarkers. 10.3389/fphar.2018.01295
Role of peptide transporters in small peptide uptake of bovine mammary epithelial cells cultured in a transwell chamber. Food science & nutrition Small peptides can be absorbed by the bovine mammary gland for the synthesis of milk protein, but the absorption mechanism still needs further study. In this study, the role of peptide transporters in small peptide uptake by bovine mammary epithelial cells (BMECs) was studied. First, BMECs were obtained and cultured in a transwell chamber. After 5 days of culture, the FITC-dextran permeability of the cell layer was detected. Then, 0.5 mM methionyl-methionine (Met-Met) was added to the medium of the lower and upper transwell chambers, respectively. The culture medium and BMECs were collected after 24 h of treatment. Liquid chromatography-mass spectrometry (LC-MS) was used to detect the concentration of Met-Met in the culture medium. Real-time PCR was used to detect the mRNA abundance of β-casein, oligopeptide transporter 2 (PepT2), and small peptide histidine transporter 1 (PhT1) in BMECs. Then, the BMECs were transfected with siRNA-PepT2 and siRNA-PhT1, respectively, and the uptake of β-Ala-Lys-N-7-amino-4-methylcoumarin-3-acetic acid (β-Ala-Lys-AMCA) in BMECs was detected. The results showed that, after 5 days of culture, the FITC-dextran permeability of BMECs was 0.6%, which was significantly lower than that of the control group. The absorption rates of Met-Met in the culture medium of the upper and lower chambers were 99.99% and 99.95%, respectively. The addition of Met-Met to the upper chamber significantly increased the mRNA abundance of β-casein and PepT2. The addition of Met-Met to the lower chamber significantly improved the mRNA abundance of β-casein, PepT2, and PhT1. The uptake of β-Ala-Lys-AMCA significantly decreased in BMECs transfected with siRNA-PepT2. These results suggested that the BMECs were successfully cultured in the transwell chamber and formed a cell layer with little permeability. The small peptides in both the upper and lower chambers of the transwell can be absorbed by BMECs in different ways. PepT2 plays an important role in the uptake of small peptides on both the basal and apical sides of BMECs, and PhT1 may be involved in the uptake of small peptides on the basal side of BMECs. Therefore, the addition of small peptides in dairy cow diets may be an effective dietary manipulation to increase milk protein concentration or yield. 10.1002/fsn3.3343
Regulatory mechanisms and function of hypoxia-induced long noncoding RNA NDRG1-OT1 in breast cancer cells. Cell death & disease Hypoxia is a classic feature of the tumor microenvironment that has profound effects on cancer progression and is tightly associated with poor prognosis. Long noncoding RNAs (lncRNAs), a component of the noncoding genome, have been increasingly investigated due to their diverse roles in tumorigenesis. Previously, a hypoxia-induced lncRNA, NDRG1-OT1, was identified in MCF-7 breast cancer cells using next-generation sequencing. However, the regulatory mechanisms of NDRG1-OT1 remain elusive. Therefore, the purpose of this study was to investigate the regulatory mechanisms and functional roles of NDRG1-OT1 in breast cancer cells. Expression profiling of NDRG1-OT1 revealed that it was upregulated under hypoxia in different breast cancer cells. Overexpression and knockdown of HIF-1α up- and downregulated NDRG1-OT1, respectively. Luciferase reporter assays and chromatin immunoprecipitation assays validated that HIF-1α transcriptionally activated NDRG1-OT1 by binding to its promoter (-1773 to -1769 and -647 to -643 bp). Next, to investigate whether NDRG1-OT1 could function as a miRNA sponge, results of in silico analysis, expression profiling of predicted miRNAs, and RNA immunoprecipitation assays indicated that NDRG1-OT1 could act as a miRNA sponge of miR-875-3p. In vitro and in vivo functional assays showed that NDRG1-OT1 could promote tumor growth and migration. Lastly, a small peptide (66 a.a.) translated from NDRG1-OT1 was identified. In summary, our findings revealed novel regulatory mechanisms of NDRG1-OT1 by HIF-1α and upon miR-875-3p. Also, NDRG1-OT1 promoted the malignancy of breast cancer cells and encoded a small peptide. 10.1038/s41419-022-05253-2
Characterisation of IL-23 receptor antagonists and disease relevant mutants using fluorescent probes. Nature communications Association of single nucleotide polymorphisms in the IL-23 receptor with several auto-inflammatory diseases, led to the heterodimeric receptor and its cytokine-ligand IL-23, becoming important drug targets. Successful antibody-based therapies directed against the cytokine have been licenced and a class of small peptide antagonists of the receptor have entered clinical trials. These peptide antagonists may offer therapeutic advantages over existing anti-IL-23 therapies, but little is known about their molecular pharmacology. In this study, we use a fluorescent version of IL-23 to characterise antagonists of the full-length receptor expressed by living cells using a NanoBRET competition assay. We then develop a cyclic peptide fluorescent probe, specific to the IL23p19:IL23R interface and use this molecule to characterise further receptor antagonists. Finally, we use the assays to study the immunocompromising C115Y IL23R mutation, demonstrating that the mechanism of action is a disruption of the binding epitope for IL23p19. 10.1038/s41467-023-38541-2
OsDSSR1, a novel small peptide, enhances drought tolerance in transgenic rice. Cui Yanchun,Li Mingjuan,Yin Xuming,Song Shufeng,Xu Guoyun,Wang Manling,Li Chunyong,Peng Can,Xia Xinjie Plant science : an international journal of experimental plant biology Small signaling peptides play important roles in plant development and responses to abiotic and biotic stresses. We have identified a novel small peptide gene in rice, OsDSSR1, which is expressed mainly in the root, stem, node, leaf, and panicle. OsDSSR1 expression is also induced by drought, salinity, ABA, and HO treatment. OsDSSR1 is localized in the nucleus and cytoplasm. Transgenic plants overexpressing OsDSSR1 exhibited enhanced drought stress tolerance and decreased ABA sensitivity as compared to the wild type. Overexpression of OsDSSR1 promoted the accumulation of compatible osmolytes, such as free proline and soluble sugars. OsDSSR1-overexpressing plants displayed enhanced OsSodCc2 and OscAPX expression and superoxide dismutase and ascorbate peroxidase activities under drought stress. RNA-sequencing data revealed that the expression of 72 abiotic stress-responsive genes was significantly altered in homozygous transgenic plants. These stress-responsive candidate genes will aid in expanding our understanding of the mechanisms by which small peptides mediate tolerance in crop species. 10.1016/j.plantsci.2018.02.015
A Novel Microparticle Based Formulation for Topical Delivery of FOL-005, a Small Peptide. Journal of pharmaceutical sciences Although many therapeutically active peptides and proteins have been developed there is a lack of topical pharmaceutical products on the market containing these sensitive molecules. The main reasons may be lack of stability and a limitation of larger molecules to penetrate into the skin. In this study we investigated the possibility to develop a peptide formulation which enables follicular permeation of peptides and passes the following criteria: 1) The formulation should be chemically and physically stable, 2) The formulation should have appealing cosmetical properties and 3) The formulation should be compatible with skin as well as sebum. The hypothesis was that increased stability of the peptide could be obtained by keeping the peptide in solid form and in a water-free environment, and that permeation into skin could be facilitated by reducing the particle size to < 10 µm and by formulating the peptide in sebum compatible excipients. By this method a safe and a cosmetically attractive formulation, facilitating the local distribution of the model peptide FOL-005 into the skin and at the same time securing chemical and physical stability, was successfully developed. 10.1016/j.xphs.2022.01.009
TP53-inducible putative long noncoding RNAs encode functional polypeptides that suppress cell proliferation. Genome research Polypeptides encoded by long noncoding RNAs (lncRNAs) are a novel class of functional molecules. However, whether these hidden polypeptides participate in the TP53 pathway and play a significant biological role is still unclear. Here, we discover that TP53-regulated lncRNAs can encode peptides, two of which are functional in various human cell lines. Using ribosome profiling and RNA-seq approaches in HepG2 cells, we systematically identified more than 300 novel TP53-regulated lncRNAs and further confirmed that 15 of these TP53-regulated lncRNAs encode peptides. Furthermore, several peptides were validated by mass spectrometry. Ten of the novel translational lncRNAs are directly inducible by TP53 in response to DNA damage. We show that the TP53-inducible peptides TP53LC02 and TP53LC04, but not their lncRNAs, can suppress cell proliferation. TP53LC04 peptide also has a function associated with cell proliferation by regulating the cell cycle in response to DNA damage. This study shows that TP53-regulated lncRNAs can encode new functional peptides, leading to the expansion of the TP53 tumor-suppressor network and providing novel potential targets for cancer therapy. 10.1101/gr.275831.121
A short ORF-encoded transcriptional regulator. Proceedings of the National Academy of Sciences of the United States of America Recent technological advances have expanded the annotated protein coding content of mammalian genomes, as hundreds of previously unidentified, short open reading frame (ORF)-encoded peptides (SEPs) have now been found to be translated. Although several studies have identified important physiological roles for this emerging protein class, a general method to define their interactomes is lacking. Here, we demonstrate that genetic incorporation of the photo-crosslinking noncanonical amino acid AbK into SEP transgenes allows for the facile identification of SEP cellular interaction partners using affinity-based methods. From a survey of seven SEPs, we report the discovery of short ORF-encoded histone binding protein (SEHBP), a conserved microprotein that interacts with chromatin-associated proteins, localizes to discrete genomic loci, and induces a robust transcriptional program when overexpressed in human cells. This work affords a straightforward method to help define the physiological roles of SEPs and demonstrates its utility by identifying SEHBP as a short ORF-encoded transcription factor. 10.1073/pnas.2021943118
Comprehensive analysis of peptide-coding genes and initial characterization of an LRR-only microprotein in . Frontiers in plant science In the past two decades, many plant peptides have been found to play crucial roles in various biological events by mediating cell-to-cell communications. However, a large number of small open reading frames (sORFs) or short genes capable of encoding peptides remain uncharacterized. In this study, we examined several candidate genes for peptides conserved between two model plants: and . We examined their expression pattern in and subcellular localization using a transient assay with . We found that one candidate, Mp, was expressed in meristems, gemma cups, and male reproductive organs called antheridiophores. MpSGF10B has an N-terminal signal peptide followed by two leucine-rich repeat (LRR) domains and was secreted to the extracellular region in and . Compared with the wild type, two independent Mp mutants had a slightly increased number of antheridiophores. It was revealed in gene ontology enrichment analysis that Mp was significantly co-expressed with genes related to cell cycle and development. These results suggest that MpSGF10B may be involved in the reproductive development of . Our research should shed light on the unknown role of LRR-only proteins in land plants. 10.3389/fpls.2022.1051017
Animal models in idiopathic inflammatory myopathies: How to overcome a translational roadblock? Afzali Ali Maisam,Ruck Tobias,Wiendl Heinz,Meuth Sven G Autoimmunity reviews Idiopathic inflammatory myopathies (IIMs) encompass a heterogenic group of rare muscle diseases with common symptoms including muscle weakness and the presence of certain histological features. Since the pathogenesis remains unclear, therapeutic approaches in general comprise unspecific immunosuppression strategies that have been met with limited success. Therefore, a deeper understanding of the underlying pathophysiological mechanisms is critically required to assist in development of targeted therapies. Animal models have proven to be tremendously helpful in mechanistic studies and allow researchers to overcome the inevitable restrictions of human research. Although the number of different IIM models has drastically increased over the last few decades, a model that exhibits the phenotypical and histopathological hallmarks of IIM is still missing. Recent publications have shown promising results addressing different pathophysiological issues like mechanisms of onset, chronification or relapse in IIM. However, a standardization of the methodology is critically required in order to improve comparability and transferability among different groups. Here we provide an overview of the currently available IIM models including our own C-peptide based small-peptide model, critically discuss their advantages and disadvantages and give perspectives to their future use. 10.1016/j.autrev.2017.03.001
Small peptide inhibitor from the sequence of RUNX3 disrupts PAK1-RUNX3 interaction and abrogates its phosphorylation-dependent oncogenic function. Oncogene P21 Activated Kinase 1 (PAK1) is an oncogenic serine/threonine kinase known to play a significant role in the regulation of cytoskeleton and cell morphology. Runt-related transcription factor 3 (RUNX3) was initially known for its tumor suppressor function, but recent studies have reported the oncogenic role of RUNX3 in various cancers. Previous findings from our laboratory provided evidence that Threonine 209 phosphorylation of RUNX3 acts as a molecular switch in dictating the tissue-specific dualistic functions of RUNX3 for the first time. Based on these proofs and to explore the translational significance of these findings, we designed a small peptide (RMR) from the protein sequence of RUNX3 flanking the Threonine 209 phosphorylation site. The selection of this specific peptide from multiple possible peptides was based on their binding energies, hydrogen bonding, docking efficiency with the active site of PAK1 and their ability to displace PAK1-RUNX3 interaction in our prediction models. We found that this peptide is stable both in in vitro and in vivo conditions, not toxic to normal cells and inhibits the Threonine 209 phosphorylation in RUNX3 by PAK1. We also tested the efficacy of this peptide to block the RUNX3 Threonine 209 phosphorylation mediated tumorigenic functions in in vitro cell culture models, patient-derived explant (PDE) models and in in vivo tumor xenograft models. These results proved that this peptide has the potential to be developed as an efficient therapeutic molecule for targeting RUNX3 Threonine 209 phosphorylation-dependent tumor phenotypes. 10.1038/s41388-021-01927-x
Prediction of LncRNA-encoded small peptides in glioma and oligomer channel functional analysis using in silico approaches. Cao Yipeng,Yang Rui,Lee Imshik,Zhang Wenwen,Sun Jiana,Meng Xiangfei,Wang Wei PloS one Glioma is a lethal malignant brain cancer, and many reports have shown that abnormalities in the behavior of water and ion channels play an important role in regulating tumor proliferation, migration, apoptosis, and differentiation. Recently, new studies have suggested that some long noncoding RNAs containing small open reading frames can encode small peptides and form oligomers for water or ion regulation. However, because the peptides are difficult to identify, their functional mechanisms are far from being clearly understood. In this study, we used bioinformatics methods to identify and evaluate lncRNAs, which may encode small transmembrane peptides in gliomas. Combining ab initio homology modeling, molecular dynamics simulations, and free energy calculations, we constructed a predictive model and predicted the oligomer channel activity of peptides by identifying the lncRNA ORFs. We found that one key hub lncRNA, namely, DLEU1, which contains two smORFs (ORF1 and ORF8), encodes small peptides that form pentameric channels. The mechanics of water and ion (Na+ and Cl-) transport through this pentameric channel were simulated. The potential mean force of the H2O molecules along the two ORF-encoded peptide channels indicated that the energy barrier was different between ORF1 and ORF8. The ORF1-encoded peptide pentamer acted as a self-assembled water channel but not as an ion channel, and the ORF8 permeated neither ions nor water. This work provides new methods and theoretical support for further elucidation of the function of lncRNA-encoded small peptides and their role in cancer. Additionally, this study provides a theoretical basis for drug development. 10.1371/journal.pone.0248634
Evolutionary Characterization of the Short Protein SPAAR. Lee Jiwon,Wacholder Aaron,Carvunis Anne-Ruxandra Genes Microproteins (<100 amino acids) are receiving increasing recognition as important participants in numerous biological processes, but their evolutionary dynamics are poorly understood. SPAAR is a recently discovered microprotein that regulates muscle regeneration and angiogenesis through interactions with conserved signaling pathways. Interestingly, SPAAR does not belong to any known protein family and has known homologs exclusively among placental mammals. This lack of distant homology could be caused by challenges in homology detection of short sequences, or it could indicate a recent emergence from a noncoding sequence. By integrating syntenic alignments and homology searches, we identify SPAAR orthologs in marsupials and monotremes, establishing that SPAAR has existed at least since the emergence of mammals. SPAAR shows substantial primary sequence divergence but retains a conserved protein structure. In primates, we infer two independent evolutionary events leading to the origination of 5' elongated isoforms of SPAAR from a noncoding sequence and find evidence of adaptive evolution in this extended region. Thus, SPAAR may be of ancient origin, but it appears to be experiencing continual evolutionary innovation in mammals. 10.3390/genes12121864
Loss of NPPA-AS1 promotes heart regeneration by stabilizing SFPQ-NONO heteromer-induced DNA repair. Basic research in cardiology The role of long non-coding RNA (lncRNA) in endogenous cardiac regeneration remains largely elusive. The mammalian cardiomyocyte is capable of regeneration for a brief period after birth. This fact allows the exploration of the roles of critical lncRNAs in the regulation of cardiac regeneration. Through a cardiac regeneration model by apical resection (AR) of the left ventricle in neonatal mice, we identified an lncRNA named natriuretic peptide A antisense RNA 1 (NPPA-AS1), which negatively regulated cardiomyocyte proliferation. In neonates, NPPA-AS1 deletion did not affect heart development, but was sufficient to prolong the postnatal window of regeneration after AR. In adult mice, NPPA-AS1 deletion improved cardiac function and reduced infarct size after myocardial infarction (MI), associated with a significant improvement in cardiomyocyte proliferation. Further analysis showed that NPPA-AS1 interacted with DNA repair-related molecule splicing factor, proline- and glutamine-rich (SFPQ). A heteromer of SFPQ and non-POU domain-containing octamer-binding protein (NONO) was required for double-strand DNA break repair, but NPPA-AS1 was competitively bound with SFPQ due to the overlapped binding sites of SFPQ and NONO. NPPA-AS1 deletion promoted the binding of SFPQ-NONO heteromer, decreased DNA damage, and activated cardiomyocyte cell cycle re-entry. Together, loss of NPPA-AS1 promoted cardiomyocyte proliferation by stabilizing SFPQ-NONO heteromer-induced DNA repair and exerted a therapeutic effect against MI in adult mice. Consequently, NPPA-AS1 may be a novel target for stimulating cardiac regeneration to treat MI. 10.1007/s00395-022-00921-y
Exploring microproteins from various model organisms using the mip-mining database. BMC genomics Microproteins, prevalent across all kingdoms of life, play a crucial role in cell physiology and human health. Although global gene transcription is widely explored and abundantly available, our understanding of microprotein functions using transcriptome data is still limited. To mitigate this problem, we present a database, Mip-mining ( https://weilab.sjtu.edu.cn/mipmining/ ), underpinned by high-quality RNA-sequencing data exclusively aimed at analyzing microprotein functions. The Mip-mining hosts 336 sets of high-quality transcriptome data from 8626 samples and nine representative living organisms, including microorganisms, plants, animals, and humans, in our Mip-mining database. Our database specifically provides a focus on a range of diseases and environmental stress conditions, taking into account chemical, physical, biological, and diseases-related stresses. Comparatively, our platform enables customized analysis by inputting desired data sets with self-determined cutoff values. The practicality of Mip-mining is demonstrated by identifying essential microproteins in different species and revealing the importance of ATP15 in the acetic acid stress tolerance of budding yeast. We believe that Mip-mining will facilitate a greater understanding and application of microproteins in biotechnology. Moreover, it will be beneficial for designing therapeutic strategies under various biological conditions. 10.1186/s12864-023-09735-1
Discovery and Characterization of a High-Affinity Small Peptide Ligand, H1, Targeting FGFR2IIIc for Skin Wound Healing. Zhao Ying,Wang Qiang,Jin Yuan,Li Yadan,Nie Changjun,Huang Peipei,Li Zhixin,Zhang Bihui,Su Zijian,Hong An,Chen Xiaojia Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology BACKGROUND/AIMS:How to aid recovery from severe skin injuries, such as burns, chronic or radiation ulcers, and trauma, is a critical clinical problem. Current treatment methods remain limited, and the discovery of ideal wound-healing therapeutics has been a focus of research. Functional recombinant proteins such as basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF) have been developed for skin repair, however, some disadvantages in their use remain. This study reports the discovery of a novel small peptide targeting fibroblast growth factor receptor 2 IIIc (FGFR2IIIc) as a potential candidate for skin wound healing. METHODS:A phage-displayed peptide library was used for biopanning FGFR2IIIc-targeting small peptides. The selected small peptides binding to FGFR2IIIc were qualitatively evaluated by an enzyme-linked immunosorbent assay. Their biological function was detected by a cell proliferation assay. Among them, an optimized small peptide named H1 was selected for further study. The affinity of the H1 peptide and FGFR2IIIc was determined by an isothermal titration calorimetry device. The ability of theH1 peptide to promote skin wound repair was investigated using an endothelial cell tube formation assay and wound healing scratch assay in vitro. Subsequently, the H1 peptide was assessed using a rat skin full-thickness wound model and chorioallantoic membrane (CAM) assays in vivo. To explore its molecular mechanisms, RNA-Seq, quantitative real-time PCR, and western blot assays were performed. Computer molecular simulations were also conducted to analyze the binding model. RESULTS:We identified a novel FGFR2IIIc-targeting small peptide, called H1, with 7 amino acid residues using phage display. H1 had high binding affinity with FGFR2IIIc. The H1 peptide promoted the proliferation and motility of fibroblasts and vascular endothelial cells in vitro. In addition, the H1 peptide enhanced angiogenesis in the chick chorioallantoic membrane and accelerated wound healing in a rat full-thickness wound model in vivo. The H1 peptide activated both the PI3K-AKT and MAPK-ERK1/2 pathways and simultaneously increased the secretion of vascular endothelial growth factor. Computer analysis demonstrated that the model of H1 peptide binding to FGFR2IIIc was similar to that of FGF2 and FGFR2IIIc. CONCLUSION:The H1 peptide has a high affinity for FGFR2IIIc and shows potential as a wound healing agent. As a substitute for bFGF, it could be developed into a novel therapeutic candidate for skin wound repair in the future. 10.1159/000493287
A miRNA-Encoded Small Peptide, vvi-miPEP171d1, Regulates Adventitious Root Formation. Chen Qiu-Ju,Deng Bo-Han,Gao Jie,Zhao Zhong-Yang,Chen Zi-Li,Song Shi-Ren,Wang Lei,Zhao Li-Ping,Xu Wen-Ping,Zhang Cai-Xi,Ma Chao,Wang Shi-Ping Plant physiology One of the biggest challenges in clonal propagation of grapevine () is difficulty of rooting. Adventitious root initiation and development are the critical steps in the cutting and layering process of grapevine, but the molecular mechanism of these processes remains unclear. Previous reports have found that microRNA (miRNA)-encoded peptides (miPEPs) can regulate plant root development by increasing the transcription of their corresponding primary miRNA. Here, we report the role of a miPEP in increasing adventitious root formation in grapevine. In this study, we performed a global analysis of miPEPs in grapevine and characterized the function of vvi-miPEP171d1, a functional, small peptide encoded by primary-miR171d. There were three small open reading frames in the 500-bp upstream sequence of pre-miR171d. One of them encoded a small peptide, vvi-miPEP171d1, which could increase the transcription of Exogenous application of vvi-miPEP171d1 to grape tissue culture plantlets promoted adventitious root development by activating the expression of vvi- Interestingly, neither exogenous application of the vvi-miPEP171d1 peptide nor overexpression of the vvi-miPEP171d1 coding sequence resulted in phenotypic changes in Arabidopsis (). Similarly, application of synthetic ath-miPEP171c, the small peptide encoded by the Arabidopsis ortholog of , inhibited the growth of primary roots and induced the early initiation of lateral and adventitious roots in Arabidopsis, while it had no effect on grape root development. Our findings reveal that miPEP171d1 regulates root development by promoting expression in a species-specific manner, further enriching the theoretical research into miPEPs. 10.1104/pp.20.00197
A microprotein N1DARP encoded by LINC00261 promotes Notch1 intracellular domain (N1ICD) degradation via disrupting USP10-N1ICD interaction to inhibit chemoresistance in Notch1-hyperactivated pancreatic cancer. Cell discovery The extensively activated Notch signaling pathway in pancreatic cancer cells is important in carcinogenesis, chemoresistance, and recurrence. Targeting this pathway is a promising therapeutic strategy for pancreatic cancer; however, few successful approaches have been reported, and currently used molecular inhibitors of this pathway exhibit limited clinical benefits. In this study, we identified a previously uncharacterized microprotein, Notch1 degradation-associated regulatory polypeptide (N1DARP), encoded by LINC00261. N1DARP knockout accelerated tumor progression and enhanced stem cell properties in pancreatic cancer organoids and LSL-Kras, LSL-Trp53, and Pdx1-Cre (KPC) mice. Mechanistically, N1DARP suppressed canonical and non-canonical Notch1 pathways by competitively disrupting the interaction between N1ICD and ubiquitin-specific peptidase 10 (USP10), thereby promoting K11- and K48-linked polyubiquitination of N1ICD. To evaluate the therapeutic potential of N1DARP, we designed a cell-penetrating stapled peptide, SAH-mAH2-5, with a helical structure similar to that of N1DARP that confers remarkable physicochemical stability. SAH-mAH2-5 interacted with and promoted the proteasome-mediated degradation of N1ICD. SAH-mAH2-5 injection provided substantial therapeutic benefits with limited off-target and systemic adverse effects in Notch1-activated pancreatic cancer models. Taken together, these findings confirm that N1DARP acts as a tumor suppressor and chemosensitizer by regulating USP10-Notch1 oncogenic signaling, and suggest a promising therapeutic strategy targeting the N1DARP-N1ICD interaction in Notch1-activated pancreatic cancer. 10.1038/s41421-023-00592-6
Effect of small peptide chelated iron on growth performance, immunity and intestinal health in weaned pigs. Porcine health management BACKGROUND:Small peptide chelated iron (SPCI), a novel iron supplementation in pig diets, owns growth-enhancing characteristics. Although a number of researches have been performed, there is no clear-cut evidence to show the exact relationship between the dose and effects of small peptide chelated minerals. Therefore, we investigated the effect of dietary supplementation of SPCI at different doses in the growth performance, immunity, and intestinal health in weaned pigs. METHODS:Thirty weaned pigs were randomly assigned into five groups and feed with basal diet or the basal diet containing 50, 75, 100, or 125 mg/kg Fe as SPCI diets. The experiment lasted for 21 d and on day 22, blood samples were collected 1 h later. The tissue and intestinal mucosa samples were collected following. RESULTS:Our results showed that the feed to gain ratio (F:G) decreased with different levels of SPCI addition (P < 0.05). The average daily gain (ADG) (P < 0.05) and digestibility of crude protein (P < 0.01) decreased with 125 mg/kg SPCI addition. With dietary different levels of SPCI addition, the serum concentrations of ferritin (quadratic, P < 0.001), transferrin (quadratic, P < 0.001), iron content in liver (quadratic, P < 0.05), gallbladder (quadratic, P < 0.01) and fecal (quadratic, P < 0.01) increased quadraticly. While the iron content in tibia (P < 0.01) increased by 100 mg/kg SPCI supplementation. Dietary 75 mg/kg SPCI addition increased the serum insulin-like growth factor I (IGF-I) (P < 0.01) and SPCI (75 ~ 100 mg/kg) addition also increased the serum content of IgA (P < 0.01). The serum concentrations of IgG (quadratic, P < 0.05) and IgM (quadratic, P < 0.01) increased quadraticly by different levels of SPCI supplementation. Moreover, different levels of SPCI supplementation decreased the serum concentration of D-lactic acid (P < 0.01). The serum glutathione peroxidase (GSH-Px) (P < 0.01) elevated but the malondialdehyde (MDA) (P < 0.05) decreased by 100 mg/kg SPCI addition. Interestingly, SPCI supplementation at 75 ~ 100 mg/kg improved the intestinal morphology and barrier function, as suggested by enhanced villus height (P < 0.01) and villus height/crypt depth (V/C) (P < 0.01) in duodenum, as well as jejunum epithelium tight-junction protein ZO-1 (P < 0.01). Moreover, SPCI supplementation at 75 ~ 100 mg/kg increased the activity of duodenal lactase (P < 0.01), jejunal sucrase (P < 0.01) and ileal maltase (P < 0.01). Importantly, the expression levels of divalent metal transporter-1(DMT1) decreased with different levels of SPCI addition (P < 0.01). In addition, dietary SPCI supplementation at 75 mg/kg elevated the expression levels of critical functional genes such as peptide transporter-1(PePT1) (P = 0.06) and zinc transporter 1 (ZnT1) (P < 0.01) in ileum. The expression levels of sodium/glucose co-transporter-1 (SGLT1) in ileum (quadratic, P < 0.05) increased quadraticly by different levels of SPCI addition and amino acid transporter-1 (CAT1) in jejunum(P < 0.05) also increased by 100 mg/kg SPCI addition. CONCLUSIONS:Dietary SPCI supplementation at 75 ~ 100 mg/kg improved growth performance by elevated immunity and intestinal health. 10.1186/s40813-023-00327-9
The NBDY Microprotein Regulates Cellular RNA Decapping. Na Zhenkun,Luo Yang,Schofield Jeremy A,Smelyansky Stephanie,Khitun Alexandra,Muthukumar Sowndarya,Valkov Eugene,Simon Matthew D,Slavoff Sarah A Biochemistry Proteogenomic identification of translated small open reading frames in humans has revealed thousands of microproteins, or polypeptides of fewer than 100 amino acids, that were previously invisible to geneticists. Hundreds of microproteins have been shown to be essential for cell growth and proliferation, and many regulate macromolecular complexes. One such regulatory microprotein is NBDY, a 68-amino acid component of the human cytoplasmic RNA decapping complex. Heterologously expressed NBDY was previously reported to regulate cytoplasmic ribonucleoprotein granules known as P-bodies and reporter gene stability, but the global effect of endogenous NBDY on the cellular transcriptome remained undefined. In this work, we demonstrate that endogenous NBDY directly interacts with the human RNA decapping complex through EDC4 and DCP1A and localizes to P-bodies. Global profiling of RNA stability changes in knockout (KO) cells reveals dysregulated stability of more than 1400 transcripts. DCP2 substrate transcript half-lives are both increased and decreased in KO cells, which correlates with 5' UTR length. deletion additionally alters the stability of non-DCP2 target transcripts, possibly as a result of downregulated expression of nonsense-mediated decay factors in KO cells. We present a comprehensive model of the regulation of RNA stability by NBDY. 10.1021/acs.biochem.0c00672
Editorial: Emerging Proteins and Polypeptides Expressed by "Non-Coding RNAs". Liu Wanting,He Qing-Yu,Brunet Marie A Frontiers in cell and developmental biology 10.3389/fcell.2022.862870
Small Peptide Modulation of Fibroblast Growth Factor Receptor 3-Dependent Postnatal Lymphangiogenesis. Perrault David P,Lee Gene K,Park Sun Young,Lee Sunju,Choi Dongwon,Jung Eunson,Seong Young Jin,Park Eun Kyung,Sung Cynthia,Yu Roy,Bouz Antoun,Pourmoussa Austin,Kim Soo Jung,Hong Young-Kwon,Wong Alex K Lymphatic research and biology BACKGROUND:The fibroblast growth factor receptor (FGFR) family includes transmembrane receptors involved in a wide range of developmental and postdevelopmental biologic processes as well as a wide range of human diseases. In particular, FGFR3 has been implicated in the mechanism by which 9-cis retinoic acid (9-cisRA) induces lymphangiogenesis and improves lymphedema. The purpose of this study was to validate the efficacy of a novel small peptide FGFR3 inhibitor, peptide P3 (VSPPLTLGQLLS), and to elucidate the role of FGFR3 in 9-cisRA-induced lymphangiogenesis using this peptide. METHODS AND RESULTS:Peptide P3 effectively inhibited FGFR3 phosphorylation. In vitro, peptide P3-mediated FGFR3 inhibition did not decrease lymphatic endothelial cell (LEC) proliferation, migration, or tubule formation. However, peptide P3-mediated FGFR3 inhibition did block 9-cisRA-stimulated LEC proliferation, migration, and tubule formation. In vivo, peptide P3-mediated FGFR3 inhibition was sufficient to inhibit 9-cisRA-induced tracheal lymphangiogenesis. CONCLUSION:FGFR3 does not appear to be essential to nonpromoted LEC proliferation, migration, and tubule formation. However, FGFR3 may play a key role in LEC proliferation, migration, tubule formation, and postnatal in vivo lymphangiogenesis when pharmacologically induced by 9-cisRA. P3 may have the potential to be used as a precise regulatory control element for 9-cisRA-mediated lymphangiogenesis. 10.1089/lrb.2018.0035
Synthesis of small peptide compounds, molecular docking, and inhibitory activity evaluation against phosphatases PTP1B and SHP2. Drug design, development and therapy BACKGROUND:The protein tyrosine phosphatases PTP1B and SHP2 are promising drug targets in treatment design for breast cancer. Searching for specific inhibitors of their activity has recently become the challenge of many studies. Previous work has indicated that the promising PTP inhibitors may be small compounds that are able to bind and interact with amino residues from the binding site. PURPOSE:The main goal of our study was to synthesize and analyze the effect of selected small peptide inhibitors on oncogenic PTP1B and SHP2 enzymatic activity and viability of MCF7 breast cancer cells. We also performed computational analysis of peptides binding with allosteric sites of PTP1B and SHP2 phosphatases. METHODS:We measured the inhibitory activity of compounds utilizing recombinant enzymes and MCF7 cell line. Computational analysis involved docking studies of binding conformation and interactions of inhibitors with allosteric sites of phosphatases. RESULTS:The results showed that the tested compounds decrease the enzymatic activity of phosphatases PTP1B and SHP2 with IC values in micromolar ranges. We observed higher inhibitory activity of dipeptides than tripeptides. Phe-Asp was the most effective against SHP2 enzymatic activity, with IC=5.2±0.4 µM. Micromolar concentrations of tested dipeptides also decreased the viability of MCF7 breast cancer cells, with higher inhibitory activity observed for the Phe-Asp peptide. Moreover, the peptides tested were able to bind and interact with allosteric sites of PTP1B and SHP2 phosphatases. CONCLUSION:Our research showed that small peptide compounds can be considered for the design of specific inhibitors of oncogenic protein tyrosine phosphatases. 10.2147/DDDT.S186614
Mitoregulin Contributes to Creatine Shuttling and Cardiolipin Protection in Mice Muscle. International journal of molecular sciences Small peptides compose a large share of the mitochondrial proteome. Mitoregulin (Mtln) is a mitochondrial peptide known to contribute to the respiratory complex I functioning and other processes in mitochondria. In our previous studies, we demonstrated that knockout mice develop obesity and accumulate triglycerides and other oxidation substrates in serum, concomitant with an exhaustion of tricarboxylic acids cycle intermediates. Here we examined the functional role of Mtln in skeletal muscles, one of the major energy consuming tissues. We observed reduced muscle strength for Mtln knockout mice. Decrease of the mitochondrial cardiolipin and concomitant increase in monolysocardiolipin concentration upon inactivation is likely to be a consequence of imbalance between oxidative damage and remodeling of cardiolipin. It is accompanied by the mitochondrial creatine kinase octamer dissociation and suboptimal respiratory chain performance in knockout mice. 10.3390/ijms24087589
Purification of Gekko Small Peptide Fraction and Its Effect of Inducing Apoptosis of EC 9706 Esophageal Cancer Cells by Inhibiting PI3K/Akt/GLUT1 Signaling Pathway. Lv Xingzhi,Li Ruifang,Li Zhongjie,Wang Jiangang Chemistry & biodiversity This study aimed to isolate and purify a cytotoxic extraction from Gekko japonicus, identify its components and determine its cytotoxic activity in vitro. We isolated and identified the most potent cytotoxic Gekko small peptide LH-20-15. The identification and analysis of peptide sequences of LH-20-15 were performed by de novo peptide sequencing, and two new peptides were found. LH-20-15 significantly inhibited the proliferation of human esophageal squamous carcinoma EC 9706 cells in a dose-dependent manner. Furthermore, LH-20-15 induced apoptosis in esophageal cancer cells by activating the mitochondrial apoptotic pathway. Further research showed that LH-20-15 inhibited the PI3 K/Akt/GLUT1 signaling pathway. In conclusion, LH-20-15 from Gekko japonicus is a peptide mixture and may inhibit EC 9706 cell proliferation and induce apoptosis by activating the mitochondrial apoptotic pathway. It also regulates glucose metabolism by targeting the PI3 K/Akt/GLUT1 signaling pathway. These small peptides could be new sources of natural cytotoxic ingredients against esophageal cancer with potential drug values. 10.1002/cbdv.202000720
Phosphorylation of a Human Microprotein Promotes Dissociation of Biomolecular Condensates. Journal of the American Chemical Society Proteogenomic identification of translated small open reading frames in humans has revealed thousands of microproteins, or polypeptides of fewer than 100 amino acids, that were previously invisible to geneticists. Hundreds of microproteins have been shown to be essential for cell growth and proliferation, and many regulate macromolecular complexes. However, the vast majority of microproteins remain functionally uncharacterized, and many lack secondary structure and exhibit limited evolutionary conservation. One such intrinsically disordered microprotein is NBDY, a 68-amino acid component of membraneless organelles known as P-bodies. In this work, we show that NBDY can undergo liquid-liquid phase separation, a biophysical process thought to underlie the formation of membraneless organelles, in the presence of RNA . Phosphorylation of NBDY drives liquid phase remixing and macroscopic P-body dissociation in cells undergoing growth factor signaling and cell division. These results suggest that NBDY phosphorylation enables regulation of P-body dynamics during cell proliferation and, more broadly, that intrinsically disordered microproteins may contribute to liquid-liquid phase separation and remixing behavior to affect cellular processes. 10.1021/jacs.1c05386
Microbial and metabolomic insights into the bovine lipometabolic responses of rumen and mammary gland to zymolytic small peptide supplementation. Frontiers in veterinary science Small peptides provide the easily utilized nitrogen for rumen microbial and promote acetate generation for milk fat synthesis. However, the impacts of peptide supplements on lipometabolic processes were still unclear. Therefore, a total of 800 multiparous dairy herds (with an average live weight of 667.6 ± 39.4 kg, an average lactation of 89.3 ± 18.8 days, and an average calving parity of 2.76 ± 0.47) were randomly allocated to the control (CON) and the small peptide (SP) supplement (100 g/day for each cow) treatments, respectively. A 35-day-long feeding procedure that includes a 7-day-long pretreatment test and a 28-day-long treatment test was followed for all cows. Dry matter intake (DMI) was recorded every day and calculated by the deviation between the supply and residue, while the daily milk production was automatically recorded through the rotary milking facilities. Milk samples were collected from each replicate on the last day, followed by the milk quality and milk lipid composition measurement. Rumen fluid samples were collected on the last day through esophageal tubing 3 h after morning feeding for the determination of the underlying mechanism of the small peptide on lipid metabolism through the measurement of rumen lipometabolic-related metabolites and rumen bacterial communities. Results indicated that dry matter intake showed an increasing trend, while milk production and the milk fat content remarkably increased after SP supplement ( < 0.05). Further detailed detection showed the mainly increased milk composition focused on monounsaturated fatty acid (MUFA) and polyunsaturated fatty acid (PUFA). Acetate-producing microbes, such as , and , and butyrate-producing microbes, such as and , significantly proliferated, which causatively brought the increased ruminal content of acetate, isobutyrate, and butyrate after SP supplement ( < 0.05) compared with CON. Lipometabolic metabolites such as phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylinositol (PI), phosphatidylserine (PS), triacylglycerol (TG), and Acetyl-CoA also significantly increased after SP supplement. In summary, SP supplements help to increase milk fat content through the proliferation of rumen bacterial communities, which provided more acetate and butyrate for milk fat synthesis combined with the promotion of ruminal lipometabolism. 10.3389/fvets.2022.875741
BmNPV circular RNA-encoded peptide VSP39 promotes viral replication. International journal of biological macromolecules CircRNAs are covalently closed single-stranded circular RNA molecules, which are not easily degraded by endonucleases and play vital roles in many biological processes. Currently, most studies on circRNAs focus on endogenous circRNAs in cells, and there are few studies on virus-encoded circRNAs. In this study, a viral circRNA (circRNA-000010) derived from the region (-/bp: 114514-115,319) of the complementary strand of Bombyx mori Nucleopolyhedrovirus (BmNPV) genome was identified with the circRNA-sequencing. The authenticity of viral circRNA-000010 was further confirmed by reverse transcription PCR, reverse transcription-rolling circle amplification (TCA), in situ hybridization, immunofluorescent staining, and Northern blotting. The results of overexpression and knockdown experiments showed that circRNA-000010 promoted viral replication. Furthermore, a viral small peptide VSP39 with 39 amino acid residues translated by circRNA-000010 but not its linear molecule was confirmed. Finally, VSP39 was found to promote viral replication. Our findings indicated that a viral circRNA encoded by BmNPV promoted viral replication. These findings will provide new clues for further understanding coding information of the BmNPV genome and open a new insight for investigating host-virus interactions. 10.1016/j.ijbiomac.2022.12.173
Scoring model based on the signature of non-m6A-related neoantigen-coding lncRNAs assists in immune microenvironment analysis and TCR-neoantigen pair selection in gliomas. Journal of translational medicine BACKGROUND:Small peptides encoded by long non-coding RNAs (lncRNAs) have attracted attention for their various functions. Recent studies indicate that these small peptides participate in immune responses and antigen presentation. However, the significance of RNA modifications remains unclear. METHODS:Thirteen non-m6A-related neoantigen-coding lncRNAs were selected for analysis from the TransLnc database. Next, a neoantigen activation score (NAS) model was established based on the characteristics of the lncRNAs. Machine learning was employed to expand the model to two additional RNA-seq and two single-cell sequencing datasets for further validation. The DLpTCR algorithm was used to predict T cell receptor (TCR)-peptide binding probability. RESULTS:The non-m6A-related NAS model predicted patients' overall survival outcomes more precisely than the m6A-related NAS model. Furthermore, the non-m6A-related NAS was positively correlated with tumor cells' evolutionary level, immune infiltration, and antigen presentation. However, high NAS gliomas also showed more PD-L1 expression and high mutation frequencies of T-cell positive regulators. Interestingly, results of intercellular communication analysis suggest that T cell-high neoplastic cell interaction is weaker in both of the NAS groups which might arise from decreased IFNGR1 expression. Moreover, we identified unique TCR-peptide pairs present in all glioma samples based on peptides encoded by the 13 selected lncRNAs. And increased levels of neoantigen-active TCR patterns were found in high NAS gliomas. CONCLUSIONS:Our work suggests that non-m6A-related neoantigen-coding lncRNAs play an essential role in glioma progression and that screened TCR clonotypes might provide potential avenues for chimeric antigen receptor T cell (CAR-T) therapy for gliomas. 10.1186/s12967-022-03713-z
Shiny transcriptional junk: lncRNA-derived peptides in cancers and immune responses. Life sciences By interacting with DNA, RNA, and proteins, long noncoding RNAs (lncRNAs) have been linked to several pathological states. LncRNA-derived peptides, as a novel modality of action of lncRNAs, have recently become a research hotspot. An increasing body of evidence has demonstrated the important role of these peptides in carcinogenesis and cancer progression and immune response. This review first describes lncRNA-derived peptides, the regulators that control their translation, and the roles of these peptides in multiple biological processes and disease states including cancers. In the following section, we comprehensively analyzed the significant role lncRNA-derived peptide played in the immune response. This review provides fresh perspectives on the biological role of lncRNAs and their relationship with diseases, particularly with cancers and the immune response, providing a theoretical basis for these lncRNA-derived peptides as therapeutic and diagnostic targets in cancers and inflammatory diseases. 10.1016/j.lfs.2023.121434
Role of long non-coding RNA H19 in the development of osteoporosis. Chen Senxiang,Liu Da,Zhou Zimo,Qin Sen Molecular medicine (Cambridge, Mass.) BACKGROUND:Osteoporosis is a widespread and serious metabolic bone disease. At present, revealing the molecular mechanisms of osteoporosis and developing effective prevention and treatment methods are of great significance to health worldwide. LncRNA is a non-coding RNA peptide chain with more than 200 nucleotides. Researchers have identified many lncRNAs implicated in the development of diseases and lncRNA H19 is an example. RESULTS:A large amount of evidence supports the fact that long non-coding RNA (lncRNA) genes, such as H19, have multiple, far-reaching effects on various biological functions. It has been found that lncRNA H19 has a role in the regulation of different types of cells in the body including the osteoblasts, osteocytes, and osteoclasts found in bones. Therefore, it can be postulated that lncRNA H19 affects the incidence and development of osteoporosis. CONCLUSION:The prospect of targeting lncRNA H19 in the treatment of osteoporosis is promising because of the effects that lncRNA H19 has on the process of osteogenic differentiation. In this review, we summarize the molecular pathways and mechanisms of lncRNA H19 in the pathogenesis of osteoporosis and summarize the research progress of targeting H19 as a treatment option. Research is emerging that explores more effective treatment possibilities for bone metabolism diseases using molecular targets. 10.1186/s10020-021-00386-0
Accelerating the Screening of Small Peptide Ligands by Combining Peptide-Protein Docking and Machine Learning. International journal of molecular sciences This research introduces a novel pipeline that couples machine learning (ML), and molecular docking for accelerating the process of small peptide ligand screening through the prediction of peptide-protein docking. Eight ML algorithms were analyzed for their potential. Notably, Light Gradient Boosting Machine (LightGBM), despite having comparable F1-score and accuracy to its counterparts, showcased superior computational efficiency. LightGBM was used to classify peptide-protein docking performance of the entire tetrapeptide library of 160,000 peptide ligands against four viral envelope proteins. The library was classified into two groups, 'better performers' and 'worse performers'. By training the LightGBM algorithm on just 1% of the tetrapeptide library, we successfully classified the remaining 99%with an accuracy range of 0.81-0.85 and an F1-score between 0.58-0.67. Three different molecular docking software were used to prove that the process is not software dependent. With an adjustable probability threshold (from 0.5 to 0.95), the process could be accelerated by a factor of at least 10-fold and still get 90-95% concurrence with the method without ML. This study validates the efficiency of machine learning coupled to molecular docking in rapidly identifying top peptides without relying on high-performance computing power, making it an effective tool for screening potential bioactive compounds. 10.3390/ijms241512144
A systematic evaluation of the computational tools for lncRNA identification. Zheng Hansi,Talukder Amlan,Li Xiaoman,Hu Haiyan Briefings in bioinformatics The computational identification of long non-coding RNAs (lncRNAs) is important to study lncRNAs and their functions. Despite the existence of many computation tools for lncRNA identification, to our knowledge, there is no systematic evaluation of these tools on common datasets and no consensus regarding their performance and the importance of the features used. To fill this gap, in this study, we assessed the performance of 17 tools on several common datasets. We also investigated the importance of the features used by the tools. We found that the deep learning-based tools have the best performance in terms of identifying lncRNAs, and the peptide features do not contribute much to the tool accuracy. Moreover, when the transcripts in a cell type were considered, the performance of all tools significantly dropped, and the deep learning-based tools were no longer as good as other tools. Our study will serve as an excellent starting point for selecting tools and features for lncRNA identification. 10.1093/bib/bbab285
Identification of Microprotein-Protein Interactions via APEX Tagging. Biochemistry Microproteins are peptides and small proteins encoded by small open reading frames (smORFs). Newer technologies have led to the recent discovery of hundreds to thousands of new microproteins. The biological functions of a few microproteins have been elucidated, and these microproteins have fundamental roles in biology ranging from limb development to muscle function, highlighting the value of characterizing these molecules. The identification of microprotein-protein interactions (MPIs) has proven to be a successful approach to the functional characterization of these genes; however, traditional immunoprecipitation methods result in the enrichment of nonspecific interactions for microproteins. Here, we test and apply an in situ proximity tagging method that relies on an engineered ascorbate peroxidase 2 (APEX) to elucidate MPIs. The results demonstrate that APEX tagging is superior to traditional immunoprecipitation methods for microproteins. Furthermore, the application of APEX tagging to an uncharacterized microprotein called C11orf98 revealed that this microprotein interacts with nucleolar proteins nucleophosmin and nucleolin, demonstrating the ability of this approach to identify novel hypothesis-generating MPIs. 10.1021/acs.biochem.7b00265
Anti-Coagulant and Antimicrobial Recombinant Heparin-Binding Major Ampullate Spidroin 2 (MaSp2) Silk Protein. Mulinti Pranothi,Diekjürgen Dorina,Kurtzeborn Kristen,Balasubramanian Narayanaganesh,Stafslien Shane J,Grainger David W,Brooks Amanda E Bioengineering (Basel, Switzerland) Governed by established structure-property relationships, peptide motifs comprising major ampullate spider silk confer a balance of strength and extensibility. Other biologically inspired small peptide motifs correlated to specific functionalities can be combined within these units to create designer silk materials with new hybrid properties. In this study, a small basic peptide, (ARKKAAKA) known to both bind heparin and mimic an antimicrobial peptide, was genetically linked to a protease-resistant, mechanically robust silk-like peptide, MaSp2. Purified fusion proteins (four silk domains and four heparin-binding peptide repeats) were expressed in . Successful fusion of a MaSp2 spider silk peptide with the heparin-binding motif was shown using a variety of analytical assays. The ability of the fusion peptide to bind heparin was assessed with ELISA and was further tested for its anticoagulant property using aPTT assay. Its intrinsic property to inhibit bacterial growth was evaluated using zone of inhibition and crystal violet (CV) assays. Using this strategy, we were able to link the two types of genetic motifs to create a designer silk-like protein with improved hemocompatibility and antimicrobial properties. 10.3390/bioengineering9020046
Plant-specific small peptide AtZSP1 interacts with ROCK1 to regulate organ size in Arabidopsis. The New phytologist Organ size is an important agronomic trait. Small peptides function in various stages of plant growth, but their regulatory mechanisms in organ growth remain poorly understood. Here, we characterize a novel small peptide, AtZSP1, which positively regulates organ size in Arabidopsis. Loss-of-function mutant atzsp1-1 exhibited small organs, whereas AtZSP1 overexpression plants (p35S:AtZSP1#1) produced larger organs. Differentially expressed genes in the shoots of atzsp1-1 and p35S:AtZSP1#1 were enriched in the cytokinin pathway. Further analysis on shoots of atzsp1-1 showed that endogenous cytokinin levels were significantly reduced, consistent with reduced expression of the cytokinin response genes ARR5/6/7 and a decrease in pARR5:GUS activity. By contrast, cytokinin levels were elevated in p35S:AtZSP1#1. These results indicate that AtZSP1 affects shoot size via changes in cytokinin levels. AtZSP1 is ubiquitously expressed and encodes a 57-amino acid endomembrane-associated protein that is highly conserved among plant species. AtZSP1 interacts with ROCK1 at the endomembrane. Genetic analysis confirmed that the small organs and low cytokinin levels in atzsp1-1 shoots are partially suppressed by the rock1-4 mutation, suggesting that AtZSP1 may function in a common pathway with ROCK1 to antagonistically regulate organ growth. Our study identified an unknown small peptide, AtZSP1, and defined its function in regulating organ size in Arabidopsis. 10.1111/nph.18093
Sitagliptin Ameliorates Creb5/lncRNA ENSMUST00000213271-Mediated Vascular Endothelial Dysfunction in Obese Mice. Cardiovascular drugs and therapy PURPOSE:Obesity is mediated by the changes in dyslipidemia, oxidative stress, and inflammation, leading to vascular endothelial dysfunction. Glucagon-like peptide-1 (GLP-1) analogues and dipeptidyl peptidase-4 inhibitors prevent the development of endothelial dysfunction. However, the underlying mechanism still remains largely unclear. Long non-coding RNAs (lncRNAs), one class of non-coding small RNAs, have been shown to exert a regulatory impact on the endothelial function in obesity. This study aimed to investigate whether the elevation of GLP-1 by a DPP-4 inhibitor sitagliptin improved vascular endothelial function by modulating lncRNAs in obese mice and to clarify the underlying molecular mechanism. METHODS:Male C57BL/6J mice were fed a high-fat diet for 4 months to induce obesity and some obese mice were treated with sitagliptin for the last 1 month. Levels of total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL), and glucagon-like peptide-1 (GLP-1) in plasma were detected by ELISA. LncRNA expression profile was analyzed via microarray. Aortic relaxations were examined by myograph. Protein expressions and phosphorylations were determined using western blot. The differentially expressed lncRNAs were validated using qRT-PCR. RESULTS:Obese mice exhibited increased levels of TC and LDL, decreased concentrations of HDL and GLP-1 in plasma, and impaired aortic endothelium-dependent relaxations; such effects could be reversed by sitagliptin. Moreover, the altered expression profile of lncRNAs in the obese mouse aortae could be modulated by sitagliptin. Consistent with microarray analysis, qRT-PCR also revealed that lncRNA ENSMUST00000213271 was up-regulated in obese mouse aortae and aortic endothelial cells (ECs), which could be down-regulated by sitagliptin. Creb5 silencing reduced lncRNA ENSMUST00000213271 in obese mouse ECs. Knockdown of either Creb5 or lncRNA ENSMUST00000213271 restored the activation of AMPK/eNOS in obese mouse ECs. Furthermore, sitagliptin also suppressed Creb5 and lncRNA ENSMUST00000213271 and increased the phosphorylations of AMPK and eNOS in obese mice. CONCLUSION:Creb5/lncRNA ENSMUST00000213271 mediated vascular endothelial dysfunction through inhibiting AMPK/eNOS cascade in obesity. Elevation of GLP-1 by sitagliptin possibly improved endothelial function by suppressing Creb5/lncRNA ENSMUST00000213271 and subsequently restoring AMPK/eNOS activation in obese mice. This study will provide new evidence for the benefits of GLP-1 against vasculopathy in obesity. 10.1007/s10557-023-07436-1
MAVI1, an endoplasmic reticulum-localized microprotein, suppresses antiviral innate immune response by targeting MAVS on mitochondrion. Science advances Pattern recognition receptor-mediated innate immunity is critical for host defense against viruses. A growing number of coding and noncoding genes are found to encode microproteins. However, the landscape and functions of microproteins in responsive to virus infection remain uncharacterized. Here, we systematically identified microproteins that are responsive to vesicular stomatitis virus infection. A conserved and endoplasmic reticulum-localized membrane microprotein, MAVI1 (microprotein in antiviral immunity 1), was found to interact with mitochondrion-localized MAVS protein and inhibit MAVS aggregation and type I interferon signaling activation. The importance of MAVI1 was highlighted that viral infection was attenuated and survival rate was increased in knockout mice. A peptide inhibitor targeting the interaction between MAVI1 and MAVS activated the type I interferon signaling to defend viral infection. Our findings uncovered that microproteins play critical roles in regulating antiviral innate immune responses, and targeting microproteins might represent a therapeutic avenue for treating viral infection. 10.1126/sciadv.adg7053
Genomic insight into domestication of rubber tree. Nature communications Understanding the genetic basis of rubber tree (Hevea brasiliensis) domestication is crucial for further improving natural rubber production to meet its increasing demand worldwide. Here we provide a high-quality H. brasiliensis genome assembly (1.58 Gb, contig N50 of 11.21 megabases), present a map of genome variations by resequencing 335 accessions and reveal domestication-related molecular signals and a major domestication trait, the higher number of laticifer rings. We further show that HbPSK5, encoding the small-peptide hormone phytosulfokine (PSK), is a key domestication gene and closely correlated with the major domestication trait. The transcriptional activation of HbPSK5 by myelocytomatosis (MYC) members links PSK signaling to jasmonates in regulating the laticifer differentiation in rubber tree. Heterologous overexpression of HbPSK5 in Russian dandelion (Taraxacum kok-saghyz) can increase rubber content by promoting laticifer formation. Our results provide an insight into target genes for improving rubber tree and accelerating the domestication of other rubber-producing plants. 10.1038/s41467-023-40304-y
Identification and targeting of G-quadruplex structures in MALAT1 long non-coding RNA. Nucleic acids research RNA G-quadruplexes (rG4s) have functional roles in many cellular processes in diverse organisms. While a number of rG4 examples have been reported in coding messenger RNAs (mRNA), so far only limited works have studied rG4s in non-coding RNAs (ncRNAs), especially in long non-coding RNAs (lncRNAs) that are of emerging interest and significance in biology. Herein, we report that MALAT1 lncRNA contains conserved rG4 motifs, forming thermostable rG4 structures with parallel topology. We also show that rG4s in MALAT1 lncRNA can interact with NONO protein with high specificity and affinity in vitro and in nuclear cell lysate, and we provide cellular data to support that NONO protein recognizes MALAT1 lncRNA via rG4 motifs. Notably, we demonstrate that rG4s in MALAT1 lncRNA can be targeted by the rG4-specific small molecule, peptide, and L-aptamer, leading to the dissociation of MALAT1 rG4-NONO protein interaction. Altogether, this study uncovers new and important rG4s in MALAT1 lncRNAs, reveals their specific interactions with NONO protein, offers multiple strategies for targeting MALAT1 and its RNA-protein complex via its rG4 structure and illustrates the prevalence and significance of rG4s in ncRNAs. 10.1093/nar/gkab1208
Rapid capture of small peptide binders. Nature reviews. Chemistry 10.1038/s41570-023-00517-7
Mitoregulin: A lncRNA-Encoded Microprotein that Supports Mitochondrial Supercomplexes and Respiratory Efficiency. Cell reports Mitochondria are composed of many small proteins that control protein synthesis, complex assembly, metabolism, and ion and reactive oxygen species (ROS) handling. We show that a skeletal muscle- and heart-enriched long non-coding RNA, LINC00116, encodes a highly conserved 56-amino-acid microprotein that we named mitoregulin (Mtln). Mtln localizes to the inner mitochondrial membrane, where it binds cardiolipin and influences protein complex assembly. In cultured cells, Mtln overexpression increases mitochondrial membrane potential, respiration rates, and Ca retention capacity while decreasing mitochondrial ROS and matrix-free Ca. Mtln-knockout mice display perturbations in mitochondrial respiratory (super)complex formation and activity, fatty acid oxidation, tricarboxylic acid (TCA) cycle enzymes, and Ca retention capacity. Blue-native gel electrophoresis revealed that Mtln co-migrates alongside several complexes, including the complex I assembly module, complex V, and supercomplexes. Under denaturing conditions, Mtln remains in high-molecular-weight complexes, supporting its role as a sticky molecular tether that enhances respiratory efficiency by bolstering protein complex assembly and/or stability. 10.1016/j.celrep.2018.06.002
lncRNA-encoded pep-AP attenuates the pentose phosphate pathway and sensitizes colorectal cancer cells to Oxaliplatin. EMBO reports Oxaliplatin (L-OHP) is a standard treatment for colorectal cancer (CRC), but chemoresistance is a considerable challenge. L-OHP shows dose-dependent toxicity, and potential approaches that sensitize cancer cells to L-OHP could reduce the dosage. With the development of translatomics, it was found that some lncRNAs encode short peptides. Here, we use ribosome footprint profiling combined with lncRNA-Seq to screen 12 lncRNAs with coding potential, of which lnc-AP encodes the short peptide pep-AP, for their role in L-OHP resistance. Co-IP and LC-MS/MS data show that the TALDO1 protein interacts with pep-AP and that pep-AP suppresses the expression of TALDO1. The pep-AP/TALDO1 pathway attenuates the pentose phosphate pathway (PPP), reducing NADPH/NADP and glutathione (GSH) levels and causing ROS accumulation and apoptosis, which sensitizes CRC cells to L-OHP in vitro and in vivo. pep-AP thus might become a potential anticancer peptide for future treatments of L-OHP-resistant CRC. 10.15252/embr.202153140
Novel Insights into Mitochondrial DNA: Mitochondrial Microproteins and mtDNA Variants Modulate Athletic Performance and Age-Related Diseases. Genes Sports genetics research began in the late 1990s and over 200 variants have been reported as athletic performance- and sports injuries-related genetic polymorphisms. Genetic polymorphisms in the α-actinin-3 (ACTN3) and angiotensin-converting enzyme (ACE) genes are well-established for athletic performance, while collagen-, inflammation-, and estrogen-related genetic polymorphisms are reported as genetic markers for sports injuries. Although the Human Genome Project was completed in the early 2000s, recent studies have discovered previously unannotated microproteins encoded in small open reading frames. Mitochondrial microproteins (also called mitochondrial-derived peptides) are encoded in the mtDNA, and ten mitochondrial microproteins, such as humanin, MOTS-c (mitochondrial ORF of the 12S rRNA type-c), SHLPs 1-6 (small humanin-like peptides 1 to 6), SHMOOSE (Small Human Mitochondrial ORF Over SErine tRNA), and Gau (gene antisense ubiquitous in mtDNAs) have been identified to date. Some of those microproteins have crucial roles in human biology by regulating mitochondrial function, and those, including those to be discovered in the future, could contribute to a better understanding of human biology. This review describes a basic concept of mitochondrial microproteins and discusses recent findings about the potential roles of mitochondrial microproteins in athletic performance as well as age-related diseases. 10.3390/genes14020286
Integration of functional peptides into nucleic acid-based nanostructures. Nanoscale In many applications such as diagnostics and therapy development, small peptide fragments consisting of only a few amino acids are often attractive alternatives to bulky proteins. This is due to factors such as the ease of scalable chemical synthesis and numerous methods for their discovery. One drawback of using peptides is that their activity can often be negatively impacted by the lack of a rigid, 3D stabilizing structure provided by the rest of the protein. In many cases, this can be alleviated by different methods of rational templating onto nanomaterials, which provides additional possibilities to use concepts of multivalence or rational nano-engineering to enhance or even create new types of function or structure. In recent years, nanostructures made from the self-assembly of DNA strands have been used as scaffolds to create functional arrangements of peptides, often leading to greatly enhanced biological activity or new material properties. This review will give an overview of nano-templating approaches based on the combination of DNA nanotechnology and peptides. This will include both bioengineering strategies to control interactions with cells or other biological systems, as well as examples where the combination of DNA and peptides has been leveraged for the rational design of new functional materials. 10.1039/d2nr05429a
KSHV transactivator-derived small peptide traps coactivators to attenuate MYC and inhibits leukemia and lymphoma cell growth. Communications biology In herpesvirus replicating cells, host cell gene transcription is frequently down-regulated because important transcriptional apparatuses are appropriated by viral transcription factors. Here, we show a small peptide derived from the Kaposi's sarcoma-associated herpesvirus transactivator (K-Rta) sequence, which attenuates cellular MYC expression, reduces cell proliferation, and selectively kills cancer cell lines in both tissue culture and a xenograft tumor mouse model. Mechanistically, the peptide functions as a decoy to block the recruitment of coactivator complexes consisting of Nuclear receptor coactivator 2 (NCOA2), p300, and SWI/SNF proteins to the MYC promoter in primary effusion lymphoma cells. Thiol(SH)-linked alkylation for the metabolic sequencing of RNA (SLAM seq) with target-transcriptional analyses further confirm that the viral peptide directly attenuates MYC and MYC-target gene expression. This study thus provides a unique tool to control MYC activation, which may be used as a therapeutic payload to treat MYC-dependent diseases such as cancers and autoimmune diseases. 10.1038/s42003-021-02853-0
PACAP and NAP: Effect of Two Functionally Related Peptides in Diabetic Retinopathy. D'Amico Agata Grazia,Maugeri Grazia,Musumeci Giuseppe,Reglodi Dora,D'Agata Velia Journal of molecular neuroscience : MN Pituitary adenylate cyclase-activating polypeptide (PACAP) is a peptide involved in physio-pathological processes of the eye. It exerts multiple effects directly through activation of its related receptors and indirectly through increases in the synthesis of activity-dependent neuroprotective protein (ADNP). To study the role of ADNP and protect against ADNP deficiencies, a small peptide called NAP was synthetized. It includes an eight amino acid active site sequence of ADNP. In this review, we summarize the knowledge regarding the neuroprotective function played by PACAP and NAP in retinal tissue and provide an overview of the correlation between PACAP and ADNP in the context of diabetic retinopathy. 10.1007/s12031-020-01769-4
Small peptide diversification through photoredox-catalyzed oxidative C-terminal modification. Chemical science A photoredox-catalyzed oxidative decarboxylative coupling of small peptides is reported, giving access to a variety of ,-acetals. They were used as intermediates for the addition of phenols and indoles, leading to novel peptide scaffolds and bioconjugates. Amino acids with nucleophilic side chains, such as serine, threonine, tyrosine and tryptophan, could also be used as partners to access tri- and tetrapeptide derivatives with non-natural cross-linking. 10.1039/d0sc06180h
Two for one: regulatory RNAs that encode small proteins. Trends in biochemical sciences RNAs are commonly categorized as being either protein-coding mRNAs or noncoding RNAs. However, an increasing number of transcripts, in organisms ranging from bacteria to humans, are being found to have both coding and noncoding functions. In some cases, the sequences encoding the protein and the regulatory RNA functions are separated, while in other cases the sequences overlap. The protein and RNA can regulate similar or distinct pathways. Here we describe examples illustrating how these dual-function (also denoted bifunctional or dual-component) RNAs are identified and their mechanisms of action and cellular roles. We also discuss the synergy or competition between coding and RNA activity and how these regulators evolved, as well as how more dual-function RNAs might be discovered and exploited. 10.1016/j.tibs.2023.09.002
Activity-Dependent Neuroprotective Protein (ADNP): An Overview of Its Role in the Eye. International journal of molecular sciences Vision is one of the dominant senses in humans and eye health is essential to ensure a good quality of life. Therefore, there is an urgent necessity to identify effective therapeutic candidates to reverse the progression of different ocular pathologies. Activity-dependent neuroprotective protein (ADNP) is a protein involved in the physio-pathological processes of the eye. Noteworthy, is the small peptide derived from ADNP, known as NAP, which shows protective, antioxidant, and anti-apoptotic properties. Herein, we review the current state of knowledge concerning the role of ADNP in ocular pathologies, while providing an overview of eye anatomy. 10.3390/ijms232113654
Mitochondrial dysfunction and beneficial effects of mitochondria-targeted small peptide SS-31 in Diabetes Mellitus and Alzheimer's disease. Ding Xiao-Wen,Robinson Megan,Li Rongzi,Aldhowayan Hadeel,Geetha Thangiah,Babu Jeganathan Ramesh Pharmacological research Diabetes and Alzheimer's disease are common chronic illnesses in the United States and lack clearly demonstrated therapeutics. Mitochondria, the "powerhouse of the cell", is involved in the homeostatic regulation of glucose, energy, and reduction/oxidation reactions. The mitochondria has been associated with the etiology of metabolic and neurological disorders through a dysfunction of regulation of reactive oxygen species. Mitochondria-targeted chemicals, such as the Szeto-Schiller-31 peptide, have advanced therapeutic potential through the inhibition of oxidative stress and the restoration of normal mitochondrial function as compared to traditional antioxidants, such as vitamin E. In this article, we summarize the pathophysiological relevance of the mitochondria and the beneficial effects of Szeto-Schiller-31 peptide in the treatment of Diabetes and Alzheimer's disease. 10.1016/j.phrs.2021.105783
Chemical labeling and proteomics for characterization of unannotated small and alternative open reading frame-encoded polypeptides. Biochemical Society transactions Thousands of unannotated small and alternative open reading frames (smORFs and alt-ORFs, respectively) have recently been revealed in mammalian genomes. While hundreds of mammalian smORF- and alt-ORF-encoded proteins (SEPs and alt-proteins, respectively) affect cell proliferation, the overwhelming majority of smORFs and alt-ORFs remain uncharacterized at the molecular level. Complicating the task of identifying the biological roles of smORFs and alt-ORFs, the SEPs and alt-proteins that they encode exhibit limited sequence homology to protein domains of known function. Experimental techniques for the functionalization of these gene classes are therefore required. Approaches combining chemical labeling and quantitative proteomics have greatly advanced our ability to identify and characterize functional SEPs and alt-proteins in high throughput. In this review, we briefly describe the principles of proteomic discovery of SEPs and alt-proteins, then summarize how these technologies interface with chemical labeling for identification of SEPs and alt-proteins with specific properties, as well as in defining the interactome of SEPs and alt-proteins. 10.1042/BST20221074
Regulatory mechanisms and clinical perspectives of circRNA in digestive system neoplasms. Sun Zhenqiang,Chen Chen,Su Yingfeng,Wang Weiwei,Yang Shuaixi,Zhou Quanbo,Wang Guixian,Li Zhen,Song Junmin,Zhang Zhiyong,Yuan Weitang,Liu Jinbo Journal of Cancer A new star, circular RNA (circRNA), is a class of noncoding RNA with a stable cyclic structure. Exonic circRNA mainly exists in the eukaryotic cytoplasm. Intronic circRNAs (ciRNA) and exonic circRNAs with introns (EIciRNA) are found in the nucleus. Recent evidences showed the functional diversity of circRNAs, which could be microRNA (miRNA) sponges, interact with protein or translate into small peptide. Due to the change of human eating habits, digestive cancer remains one of the most common cancers worldwide and it is prone to metastasis. Increasing studies have found a number of circRNAs using RNA sequencing technology and displayed double roles of circRNA in digestive cancer. In this review, we surveyed the biogenesis and regulation of circRNAs, discussed circRNA functions and clinical applications (especially circRNAs in exosome) in digestive cancers, which implied that circRNAs could be as potential biomarkers in diagnosis and treatment of digestive cancers in the future. 10.7150/jca.31167
Synthesis and characterization of a photocleavable collagen-like peptide. Organic & biomolecular chemistry A 34-amino acid long collagen-like peptide rich in proline, hydroxyproline, and glycine, and with four photoreactive N-acyl-7-nitroindoline units incorporated into the peptide backbone was synthesized by on-resin fragment condensation. Its circular dichroism supports a stable triple helix structure. The built-in photochemical function enables the decomposition of the peptide into small peptide fragments by illumination with UV light of 350 nm in aqueous solution. Illumination of a thin film of the peptide, or a thin film of a photoreactive amino acid model compound containing a 5-bromo-7-nitroindoline moiety, with femtosecond laser light at 710 nm allows for the creation of well-resolved micropatterns. The cytocompatibility of the peptide was demonstrated using human mesenchymal stem cells and mouse embryonic fibroblasts. Our data show that the full-length peptide is cytocompatible as it can support cell growth and maintain cell viability. In contrast, the small peptide fragments created by photolysis are somewhat cytotoxic and therefore less cytocompatible. These data suggest that biomimetic collagen-like photoreactive peptides could potentially be used for growing cells in 2D micropatterns based on patterns generated by photolysis prior to cell growth. 10.1039/c7ob02198d
Effects of Small Peptide Supplementation on Growth Performance, Intestinal Barrier of Laying Hens During the Brooding and Growing Periods. Frontiers in immunology The growing period is a critical period for growth and development in laying hens. During this period, chicks grow rapidly, but are accompanied by unstable digestive function, incomplete organ development, and high mortality. Small peptide, a feed additive, which has been proved to promote intestinal development and immunity in poultry. In order to elucidate the effects of small peptides on growth performance, immunity, antioxidant capacity, and intestinal health of growing laying hens, a total of 900 Tianfu green shell laying hens (1-day-old) were randomly divided into 5 treatments with 6 replicates of 30 birds each in this 18-week trial. Dietary treatments included a corn-soybean meal-based diet supplemented with 0 g/kg, 1.5 g/kg, 3.0 g/kg, 4.5 g/kg and 6.0 g/kg small peptide, respectively. The results showed that the supplementation of small peptides significantly increased growth rate (<0.05) in laying hens, as well as elevated the serum immunoglobulins (<0.05) and antioxidant indices (<0.05), however, it decreased inflammation parameters (<0.05). The supplementation of small peptides enhanced the intestinal function by promoting gut development (<0.05) and improving gut integrity (<0.05), barrier function (<0.05) and the diversity of gut microbiota (<0.05) in the growing hens. The best performance was recorded among the hens fed 4.5 g/kg level of small peptide. Taken together, these results showed that small peptide supplementation could improve the economic value of growing hens by promoting growth rate, disease resistance, and the optimal amount of addition for Tianfu green shell laying hens was 4.5 g/kg. 10.3389/fimmu.2022.925256
The effect of C-peptide on diabetic nephropathy: A review of molecular mechanisms. Yaribeygi Habib,Maleki Mina,Sathyapalan Thozhukat,Sahebkar Amirhossein Life sciences C-peptide is a small peptide connecting two chains of proinsulin molecule and is dissociated before the release of insulin. It is secreted in an equimolar amount to insulin from the pancreatic beta-cells into the circulation. Recent evidence demonstrates that it has other physiologic activities beyond its structural function. C-peptide modulates intracellular signaling pathways in various pathophysiologic states and, could potentially be a new therapeutic target for different disorders including diabetic complications. There is growing evidence that c-peptide has modulatory effects on the molecular mechanisms involved in the development of diabetic nephropathy. Although we have little direct evidence, pharmacological properties of c-peptide suggest that it can provide potent renoprotective effects especially, in a c-peptide deficient milieu as in type 1 diabetes mellitus. In this review, we describe possible molecular mechanisms by which c-peptide may improve renal efficiency in a diabetic milieu. 10.1016/j.lfs.2019.116950
Dissecting the Conformational Free Energy of a Small Peptide in Solution. Fajardo Tawny N,Heyden Matthias The journal of physical chemistry. B The free energy surface of a small peptide was analyzed based on an unbiased microsecond molecular dynamics simulation. The peptide sampled disordered conformational ensembles of distinct compactness, and its free energy was decomposed into separate contributions from the intramolecular potential energy, conformational entropy, and solvation free energy. The latter was further broken down into enthalpic and entropic contributions due to peptide-water and water-water interactions. This decomposition was enabled by a generalized linear response relation between the peptide-water interaction energy and the solvation free energy, which was empirically parametrized by explicit solvation free energy calculations for representative peptide conformations. This full dissection of the peptide free energy identifies individual contributions that stabilize and destabilize compact and extended peptide conformational ensembles and reveals the origin of a free energy barrier associated with transitions between them. 10.1021/acs.jpcb.1c00699
Potent Lys Patch-Containing Stapled Peptides Targeting PCSK9. Bourbiaux Kévin,Legrand Baptiste,Verdié Pascal,Mallart Sergio,Manette Géraldine,Minoletti Claire,Stepp J David,Prigent Philippe,Le Bail Jean-Christophe,Gauzy-Lazo Laurence,Duclos Olivier,Martinez Jean,Amblard Muriel Journal of medicinal chemistry Proprotein convertase subtilisin/kexin type 9 (PCSK9), identified as a regulator of low-density lipoprotein receptor (LDLR), plays a major role in cardiovascular diseases (CVD). Recently, Pep2-8, a small peptide with discrete three-dimensional structure, was found to inhibit the PCSK9/LDLR interaction. In this paper, we describe the modification of this peptide using stapled peptide and SIP technologies. Their combination yielded potent compounds such as that potently inhibited the binding of PCSK9 to LDLR ( = 6 ± 1 nM) and restored in vitro LDL uptake by HepG2 cells in the presence of PCSK9 (EC = 175 ± 40 nM). The three-dimensional structures of key peptides were extensively studied by circular dichroism and nuclear magnetic resonance, and molecular dynamics simulations allowed us to compare their binding mode to tentatively rationalize structure-activity relationships (SAR). 10.1021/acs.jmedchem.0c02051
Significance of LL-37 on Immunomodulation and Disease Outcome. BioMed research international LL-37, also called cathelicidin, is an important part of the human immune system, which can resist various pathogens. A plethora of experiments have demonstrated that it has the multifunctional effects of immune regulation, in addition to antimicrobial activity. Recently, there have been increasing interest in its immune function. It was found that LL-37 can have two distinct functions in different tissues and different microenvironments. Thus, it is necessary to investigate LL-37 immune functions from the two sides of the same coin. On the one side, LL-37 promotes inflammation and immune response and exerts its anti-infective and antitumor effects; on the other side, it has the ability to inhibit inflammation and promote carcinogenesis. This review presents a brief summary of its expression, structure, and immunomodulatory effects as well as brief discussions on the role of this small peptide as a key factor in the development and treatment of various inflammation-related diseases and cancers. 10.1155/2020/8349712
Approaches to identify and characterize microProteins and their potential uses in biotechnology. Cellular and molecular life sciences : CMLS MicroProteins are small proteins that contain a single protein domain and are related to larger, often multi-domain proteins. At the molecular level, microProteins act by interfering with the formation of higher order protein complexes. In the past years, several microProteins have been identified in plants and animals that strongly influence biological processes. Due to their ability to act as dominant regulators in a targeted manner, microProteins have a high potential for biotechnological use. In this review, we present different ways in which microProteins are generated and we elaborate on techniques used to identify and characterize them. Finally, we give an outlook on possible applications in biotechnology. 10.1007/s00018-018-2818-8
Use of Peptide Libraries for Identification and Optimization of Novel Antimicrobial Peptides. Ashby Martin,Petkova Asya,Gani Jurnorain,Mikut Ralf,Hilpert Kai Current topics in medicinal chemistry The increasing rates of resistance among bacteria and to a lesser extent fungi have resulted in an urgent need to find new molecules that hold therapeutic promise against multidrug-resistant strains. Antimicrobial peptides have proven very effective against a variety of multidrug-resistant bacteria. Additionally, the low levels of resistance reported towards these molecules are an attractive feature for antimicrobial drug development. Here we summarise information on diverse peptide libraries used to discover or to optimize antimicrobial peptides. Chemical synthesized peptide libraries, for example split and mix method, tea bag method, multi-pin method and cellulose spot method are discussed. In addition biological peptide library screening methods are summarized, like phage display, bacterial display, mRNA-display and ribosomal display. A few examples are given for small peptide libraries, which almost exclusively follow a rational design of peptides of interest rather than a combinatorial approach.
TransLnc: a comprehensive resource for translatable lncRNAs extends immunopeptidome. Lv Dezhong,Chang Zhenghong,Cai Yangyang,Li Junyi,Wang Liping,Jiang Qiushuang,Xu Kang,Ding Na,Li Xia,Xu Juan,Li Yongsheng Nucleic acids research LncRNAs are not only well-known as non-coding elements, but also serve as templates for peptide translation, playing important roles in fundamental cellular processes and diseases. Here, we describe a database, TransLnc (http://bio-bigdata.hrbmu.edu.cn/TransLnc/), which aims to provide comprehensive experimentally supported and predicted lncRNA peptides in multiple species. TransLnc currently documents approximate 583 840 peptides encoded by 33 094 lncRNAs. Six types of direct and indirect evidences supporting the coding potential of lncRNAs were integrated, and 65.28% peptides entries were with at least one type of evidence. Considering the strong tissue-specific expression of lncRNAs, TransLnc allows users to access lncRNA peptides in any of the 34 tissues involved in. In addition, both the unique characteristic and homology relationship were also predicted and provided. Importantly, TransLnc provides computationally predicted tumour neoantigens from peptides encoded by lncRNAs, which would provide novel insights into cancer immunotherapy. There were 220 791 and 237 915 candidate neoantigens binding by major histocompatibility complex (MHC) class I or II molecules, respectively. Several flexible tools were developed to aid retrieve and analyse, particularly lncRNAs tissue expression patterns, clinical relevance across cancer types. TransLnc will serve as a valuable resource for investigating the translation capacity of lncRNAs and greatly extends the cancer immunopeptidome. 10.1093/nar/gkab847
Quantifying telomeric lncRNAs using PNA-labelled RNA-Flow FISH (RNA-Flow). Communications biology Here we present a method to detect and quantify long non-coding RNAs, in particular those related to telomeres. By coupling the specificity of a peptide nucleic acid (PNA) probe with flow cytometry we have quantified cellular levels of TERRA and TERC lncRNAs in culture cell lines and PBMCs. This easy-to-use method appointed RNA-Flow allows reliable lncRNA quantification with broad applications in basic research and clinical diagnostics. In addition, the staining protocol presented here was proven useful for the detection and quantification of such lncRNAs on unfixed cells using confocal microscopy. 10.1038/s42003-022-03452-3
Small peptide LINC00511-133aa encoded by LINC00511 regulates breast cancer cell invasion and stemness through the Wnt/β-catenin pathway. Molecular and cellular probes LINC00511 is an long non-coding RNA (lncRNA) of ncRNAs,This study aimed to investigate whether the lncRNA LINC00511 could encode a small peptide, LINC00511-133aa, and whether this peptide could promote breast cancer cell metastasis and stemness by activating the wnt/β-catenin pathway. The LINC00511-133aa coding sequence vector and control vector were transfected into MCF-7 and MDA-MB-231 breast cancer cells, with subsequent assessment of peptide expression using PCR, western blotting, and immunofluorescence assays. Cell proliferation, invasion, and apoptosis were evaluated using CCK8, apoptotic, wound healing, and transwell invasion assays, while the characteristic changes of tumor stem cells were detected through sphere-forming assay and western blot analyses of the stemness markers Oct4, Nanog, and SOX2. Results showed that LINC00511-133aa was indeed encoded by LINC00511 and promoted the invasiveness and stemness of breast cancer cells while limiting apoptosis by modulating the expression levels of wnt/β-catenin pathway-related proteins Bax, c-myc, and CyclinD1, as well as facilitating β-catenin protein entry into the nucleus. This study provides evidence for the potential involvement of lncRNA LINC00511 and its peptide product in breast cancer progression via the regulation of the wnt/β-catenin pathway. 10.1016/j.mcp.2023.101913
Hundreds of LncRNAs Display Circadian Rhythmicity in Zebrafish Larvae. Mishra Shital Kumar,Zhong Zhaomin,Wang Han Cells Long noncoding RNAs (lncRNAs) have been shown to play crucial roles in various life processes, including circadian rhythms. Although next generation sequencing technologies have facilitated faster profiling of lncRNAs, the resulting datasets require sophisticated computational analyses. In particular, the regulatory roles of lncRNAs in circadian clocks are far from being completely understood. In this study, we conducted RNA-seq-based transcriptome analysis of zebrafish larvae under both constant darkness (DD) and constant light (LL) conditions in a circadian manner, employing state-of-the-art computational approaches to identify approximately 3220 lncRNAs from zebrafish larvae, and then uncovered 269 and 309 lncRNAs displaying circadian rhythmicity under DD and LL conditions, respectively, with 30 of them are coexpressed under both DD and LL conditions. Subsequently, GO, COG, and KEGG pathway enrichment analyses of all these circadianly expressed lncRNAs suggested their potential involvement in numerous biological processes. Comparison of these circadianly expressed zebrafish larval lncRNAs, with rhythmically expressed lncRNAs in the zebrafish pineal gland and zebrafish testis, revealed that nine (DD) and twelve (LL) larval lncRNAs are coexpressed in the zebrafish pineal gland and testis, respectively. Intriguingly, among peptides encoded by these coexpressing circadianly expressed lncRNAs, three peptides (DD) and one peptide (LL) were found to have the known domains from the Protein Data Bank. Further, the conservation analysis of these circadianly expressed zebrafish larval lncRNAs with human and mouse genomes uncovered one lncRNA and four lncRNAs shared by all three species under DD and LL conditions, respectively. We also investigated the conserved lncRNA-encoded peptides and found one peptide under DD condition conserved in these three species and computationally predicted its 3D structure and functions. Our study reveals that hundreds of lncRNAs from zebrafish larvae exhibit circadian rhythmicity and should help set the stage for their further functional studies. 10.3390/cells10113173
Editorial: Novel Therapeutic Target and Drug Development in Neurovascular Retinal Diseases. Shao Zhuo,Wang Zhongxiao,Lo Amy C Y,Fu Zhongjie Frontiers in pharmacology 10.3389/fphar.2021.657684
Insights from Self-Assembled Aggregates of Amyloid β Peptides on Gold Surfaces. Dey Chinmay,Roy Madhuparna,Dey Somdatta Ghosh ACS omega Amyloid β (Aβ) peptides mutated at different positions using a cysteine moiety assemble on Au electrodes using the thiol functionality of cysteine. Self-assembled monolayers (SAMs) of Aβ on Au surfaces can act as abiological platforms that allow the mimicking of fibrils and oligomeric Aβ via the formation of controlled large and small peptide aggregates. These Aβ constructs bind with heme and Cu and exhibit different reactivities. These abiological platforms can also be used to investigate potential drugs that can interact with heme and Cu-Aβ. SAM formation of Aβ mutants allows the study of different morphology and structure as well as behavior changes on binding with different metals and cytochrome (Cyt ). This review provides a detailed insight into the structure and reactivities of various Aβ aggregated on Au electrodes mimicking the cell membrane. 10.1021/acsomega.1c06056
Cross-Species Genome-Wide Identification of Evolutionary Conserved MicroProteins. Straub Daniel,Wenkel Stephan Genome biology and evolution MicroProteins are small single-domain proteins that act by engaging their targets into different, sometimes nonproductive protein complexes. In order to identify novel microProteins in any sequenced genome of interest, we have developed miPFinder, a program that identifies and classifies potential microProteins. In the past years, several microProteins have been discovered in plants where they are mainly involved in the regulation of development by fine-tuning transcription factor activities. The miPFinder algorithm identifies all up to date known plant microProteins and extends the microProtein concept beyond transcription factors to other protein families. Here, we reveal potential microProtein candidates in several plant and animal reference genomes. A large number of these microProteins are species-specific while others evolved early and are evolutionary highly conserved. Most known microProtein genes originated from large ancestral genes by gene duplication, mutation and subsequent degradation. Gene ontology analysis shows that putative microProtein ancestors are often located in the nucleus, and involved in DNA binding and formation of protein complexes. Additionally, microProtein candidates act in plant transcriptional regulation, signal transduction and anatomical structure development. MiPFinder is freely available to find microProteins in any genome and will aid in the identification of novel microProteins in plants and animals. 10.1093/gbe/evx041
LncPep: A Resource of Translational Evidences for lncRNAs. Liu Teng,Wu Jingni,Wu Yangjun,Hu Wei,Fang Zhixiao,Wang Zishan,Jiang Chunjie,Li Shengli Frontiers in cell and developmental biology Long noncoding RNAs (lncRNAs) are a type of transcript that is >200 nucleotides long with no protein-coding capacity. Accumulating studies have suggested that lncRNAs contain open reading frames (ORFs) that encode peptides. Although several noncoding RNA-encoded peptide-related databases have been developed, most of them display only a small number of experimentally validated peptides, and resources focused on lncRNA-encoded peptides are still lacking. We used six types of evidence, coding potential assessment tool (CPAT), coding potential calculator v2.0 (CPC2), N6-methyladenosine modification of RNA sites (m6A), Pfam, ribosome profiling (Ribo-seq), and translation initiation sites (TISs), to evaluate the coding potential of 883,804 lncRNAs across 39 species. We constructed a comprehensive database of lncRNA-encoded peptides, LncPep (http://www.shenglilabs.com/LncPep/). LncPep provides three major functional modules: 1) user-friendly searching/browsing interface, 2) prediction and BLAST modules for exploring novel lncRNAs and peptides, and 3) annotations for lncRNAs, peptides and supporting evidence. Taken together, LncPep is a user-friendly and convenient platform for discovering and investigating peptides encoded by lncRNAs. 10.3389/fcell.2022.795084
Non-coding transcript variants of protein-coding genes - what are they good for? Dhamija Sonam,Menon Manoj B RNA biology The total number of protein-coding genes in the human genome is not significantly higher than those in much simpler eukaryotes, despite a general increase in genome size proportionate to the organismal complexity. The large non-coding transcriptome and extensive differential splicing, are increasingly being accepted as the factors contributing to the complex mammalian physiology and architecture. Recent studies reveal additional layers of functional complexity: some long non-coding RNAs have been re-defined as micropeptide or microprotein encoding transcripts, and in turn some protein-coding RNAs are bifunctional and display also non-coding functions. Moreover, several protein-coding genes express long non-coding RNA splice-forms and generate circular RNAs in addition to their canonical mRNA transcripts, revoking the strict definition of a gene as coding or non-coding. In this mini review, we discuss the current understanding of these hybrid genes and their possible roles and relevance. 10.1080/15476286.2018.1511675
Identification and analysis of smORFs in Chlamydomonas reinhardtii. Genomics Small open reading frames (smORFs) have been acknowledged as an important partner in organism functions ranging from bacteria to higher eukaryotes. However, there is a lack of investigation of smORFs in green algae, despite their importance in ecology and evolution. We applied bioinformatic analysis, ribosome profiling, and small peptide proteomics to provide a genome-wide and high-confident smORF database in the model green alga Chlamydomonas reinhardtii. The whole genome was screened first to mine potential coding smORFs. Then conservative analysis, ribosome profiling, and proteomics data were processed to identify conserved smORFs and generate translation evidence. The combination of procedures resulted in 2014 smORFs that might exist in the C. reinhardtii genome. The expression of smORFs in Cd treatment suggested that two smORFs might participate in redox reaction, three in inorganic phosphate transport, and one in DNA repair under stress. Our study built a genome-widely database in C. reinhardtii, providing target smORFs for further research. 10.1016/j.ygeno.2022.110444
Exploring fungal RiPPs from the perspective of chemical ecology. Fungal biology and biotechnology Since the initial detection, in 2007, of fungal ribosomally synthesised and post-translationally modified peptides (RiPPs), this group of natural products has undergone rapid expansion, with four separate classes now recognised: amatoxins/phallotoxins, borosins, dikaritins, and epichloëcyclins. Largely due to their historically anthropocentric employment in medicine and agriculture, novel fungal proteins and peptides are seldom investigated in relation to the fungus itself. Therefore, although the benefits these compounds confer to humans are often realised, their evolutionary advantage to the fungus, the reason for their continued production, is often obscure or ignored. This review sets out to summarise current knowledge on how these small peptide-derived products influence their producing species and surrounding biotic environment. 10.1186/s40694-022-00144-9
Ghrelin octanoylation by ghrelin -acyltransferase: Unique protein biochemistry underlying metabolic signaling. Hougland James L Biochemical Society transactions Ghrelin is a small peptide hormone that requires a unique post-translational modification, serine octanoylation, to bind and activate the GHS-R1a receptor. Ghrelin signaling is implicated in a variety of neurological and physiological processes, but is most well known for its roles in controlling hunger and metabolic regulation. Ghrelin octanoylation is catalyzed by ghrelin -acyltransferase (GOAT), a member of the membrane-bound -acyltransferase (MBOAT) enzyme family. From the status of ghrelin as the only substrate for GOAT in the human genome to the source and requirement for the octanoyl acyl donor, the ghrelin-GOAT system is defined by multiple unique aspects within both protein biochemistry and endocrinology. In this review, we examine recent advances in our understanding of the interactions and mechanisms leading to ghrelin modification by GOAT, discuss the potential sources for the octanoyl acyl donor required for ghrelin's activation, and summarize the current landscape of molecules targeting ghrelin octanoylation through GOAT inhibition. 10.1042/BST20180436
A Small Peptide Increases Drug Delivery in Human Melanoma Cells. Pharmaceutics Melanoma is the most fatal type of skin cancer and is notoriously resistant to chemotherapies. The response of melanoma to current treatments is difficult to predict. To combat these challenges, in this study, we utilize a small peptide to increase drug delivery to melanoma cells. A peptide library array was designed and screened using a peptide array-whole cell binding assay, which identified KK-11 as a novel human melanoma-targeting peptide. The peptide and its D-amino acid substituted analogue (VPWxEPAYQrFL or D-aa KK-11) were synthesized via a solid-phase strategy. Further studies using FITC-labeled KK-11 demonstrated dose-dependent uptake in human melanoma cells. D-aa KK-11 significantly increased the stability of the peptide, with 45.3% remaining detectable after 24 h with human serum incubation. Co-treatment of KK-11 with doxorubicin was found to significantly enhance the cytotoxicity of doxorubicin compared to doxorubicin alone, or sequential KK-11 and doxorubicin treatment. In vivo and ex vivo imaging revealed that D-aa KK-11 distributed to xenografted A375 melanoma tumors as early as 5 min and persisted up to 24 h post tail vein injection. When co-administered, D-aa KK-11 significantly enhanced the anti-tumor activity of a novel nNOS inhibitor (MAC-3-190) in an A375 human melanoma xenograft mouse model compared to MAC-3-190 treatment alone. No apparent systemic toxicities were observed. Taken together, these results suggest that KK-11 may be a promising human melanoma-targeted delivery vector for anti-melanoma cargo. 10.3390/pharmaceutics14051036
Advancement from Small Peptide Pharmaceuticals to Orally Active Piperazine-2,5-dion-Based Cyclopeptides. International journal of molecular sciences The oral delivery of peptide pharmaceuticals has long been a fundamental challenge in drug development. A new chemical platform was designed based on branched piperazine-2,5-diones for creating orally available biologically active peptidomimetics. The platform includes a bio-carrier with "built-in" functionally active peptide fragments or bioactive molecules that are covalently attached via linkers. The developed platform allows for a small peptide to be taken with a particular biological activity and to be transformed into an orally stable compound displaying the same activity. Based on this approach, various peptidomimetics exhibiting hemostimulating, hemosuppressing, and adjuvant activity were prepared. In addition, new examples of a rare phenomenon when enantiomeric molecules demonstrate reciprocal biological activity are presented. Finally, the review summarizes the evolutionary approach of the short peptide pharmaceutical development from the immunocompetent organ separation to orally active cyclopeptides and peptidomimetics. 10.3390/ijms241713534
Long non-coding RNAs: novel regulators of cellular physiology and function. Pflugers Archiv : European journal of physiology Long non-coding RNAs were once considered as "junk" RNA produced by aberrant DNA transcription. They are now understood to play central roles in diverse cellular processes from proliferation and migration to differentiation, senescence and DNA damage control. LncRNAs are classed as transcripts longer than 200 nucleotides that do not encode a peptide. They are relevant to many physiological and pathophysiological processes through their control of fundamental molecular functions. This review summarises the recent progress in lncRNA research and highlights the far-reaching physiological relevance of lncRNAs. The main areas of lncRNA research encompassing their characterisation, classification and mechanisms of action will be discussed. In particular, the regulation of gene expression and chromatin landscape through lncRNA control of proteins, DNA and other RNAs will be introduced. This will be exemplified with a selected number of lncRNAs that have been described in numerous physiological contexts and that should be largely representative of the tens-of-thousands of mammalian lncRNAs. To some extent, these lncRNAs have inspired the current thinking on the central dogmas of epigenetics, RNA and DNA mechanisms. 10.1007/s00424-021-02641-z
A Practical Guide to Small Protein Discovery and Characterization Using Mass Spectrometry. Journal of bacteriology Small proteins of up to ∼50 amino acids are an abundant class of biomolecules across all domains of life. Yet due to the challenges inherent in their size, they are often missed in genome annotations, and are difficult to identify and characterize using standard experimental approaches. Consequently, we still know few small proteins even in well-studied prokaryotic model organisms. Mass spectrometry (MS) has great potential for the discovery, validation, and functional characterization of small proteins. However, standard MS approaches are poorly suited to the identification of both known and novel small proteins due to limitations at each step of a typical proteomics workflow, i.e., sample preparation, protease digestion, liquid chromatography, MS data acquisition, and data analysis. Here, we outline the major MS-based workflows and bioinformatic pipelines used for small protein discovery and validation. Special emphasis is placed on highlighting the adjustments required to improve detection and data quality for small proteins. We discuss both the unbiased detection of small proteins and the targeted analysis of small proteins of interest. Finally, we provide guidelines to prioritize novel small proteins, and an outlook on methods with particular potential to further improve comprehensive discovery and characterization of small proteins. 10.1128/JB.00353-21
Evaporation-Induced Self-Assembly of Small Peptide-Conjugated Silica Nanoparticles. Angewandte Chemie (International ed. in English) Self-assembly processes guide disordered molecules or particles into long-range organized structures due to specific supramolecular interactions among the building entities. Herein, we report a unique evaporation-induced self-assembly (EISA) strategy for four different silica nanoparticle systems obtained through peptide functionalization of the particle surface. First, covalent peptide-silica coupling was investigated in detail, starting with the grafting of a single amino acid (L-serine) and expanded to specific small peptides (up to four amino acids) and transferred to different particle types (MCM-48-type MSNs, solid nanoparticles, and newly developed virus-like nanoparticles). These materials were investigated regarding their ability to undergo EISA, which was shown to be independent of particle type and amount of peptide anchored to their surface. This EISA-based approach provides new possibilities for the design of future advanced drug delivery systems, engineered hierarchical sorbents, and nanocatalyst assemblies. 10.1002/anie.202108378
Cyclotides, a versatile ultrastable micro-protein scaffold for biotechnological applications. Bioorganic & medicinal chemistry letters Cyclotides are fascinating microproteins (≈30-40 residues long) with a unique head-to-tail cyclized backbone, stabilized by three disulfide bonds forming a cystine knot. This unique topology makes them exceptionally stable to chemical, thermal and biological degradation compared to other peptides of similar size. Cyclotides have been also found to be highly tolerant to sequence variability, aside from the conserved residues forming the cystine knot, able to cross cellular membranes and modulate intracellular protein-protein interactions both in vitro and in vivo. These properties make them ideal scaffolds for many biotechnological applications. This article provides and overview of the properties of cyclotides and their applications as molecular imaging agents and peptide-based therapeutics. 10.1016/j.bmcl.2017.10.051
Construction of protein assemblies by host-guest interactions with cucurbiturils. Hou Chunxi,Huang Zupeng,Fang Yu,Liu Junqiu Organic & biomolecular chemistry Protein assemblies are extremely interesting in chemistry and supramolecular chemistry. How to design protein assemblies with dimensional structures is important for applications. To address this challenge, cucurbituril (CB[n]s)-based strategies have been explored owing to their high affinity toward small peptide motifs, organic cations and amines. By incorporation of a small molecule guest and a peptide motif guest into N-terminals of oligomeric proteins, CB[n]s could recognize and bind to the N-terminal guests, leading to dimensional protein assemblies. The dimensional protein assemblies possess structural, stimuli-responsive and bioactive properties with great potential for in vivo applications. Herein, we reviewed the progress in the design of dimensional protein assemblies based on supramolecular interactions of CB[n]s and present the perspectives in the design of high-ordered biomaterials for biomedical applications. 10.1039/c7ob00686a
An Integrated Approach for Microprotein Identification and Sequence Analysis. Journal of visualized experiments : JoVE Next-generation sequencing (NGS) has propelled the field of genomics forward and produced whole genome sequences for numerous animal species and model organisms. However, despite this wealth of sequence information, comprehensive gene annotation efforts have proven challenging, especially for small proteins. Notably, conventional protein annotation methods were designed to intentionally exclude putative proteins encoded by short open reading frames (sORFs) less than 300 nucleotides in length to filter out the exponentially higher number of spurious noncoding sORFs throughout the genome. As a result, hundreds of functional small proteins called microproteins (<100 amino acids in length) have been incorrectly classified as noncoding RNAs or overlooked entirely. Here we provide a detailed protocol to leverage free, publicly available bioinformatic tools to query genomic regions for microprotein-coding potential based on evolutionary conservation. Specifically, we provide step-by-step instructions on how to examine sequence conservation and coding potential using Phylogenetic Codon Substitution Frequencies (PhyloCSF) on the user-friendly University of California Santa Cruz (UCSC) Genome Browser. Additionally, we detail steps to efficiently generate multiple species alignments of identified microprotein sequences to visualize amino acid sequence conservation and recommend resources to analyze microprotein characteristics, including predicted domain structures. These powerful tools can be used to help identify putative microprotein-coding sequences in noncanonical genomic regions or to rule out the presence of a conserved coding sequence with translational potential in a noncoding transcript of interest. 10.3791/63841
One-shot analysis of translated mammalian lncRNAs with AHARIBO. Minati Luca,Firrito Claudia,Del Piano Alessia,Peretti Alberto,Sidoli Simone,Peroni Daniele,Belli Romina,Gandolfi Francesco,Romanel Alessandro,Bernabo Paola,Zasso Jacopo,Quattrone Alessandro,Guella Graziano,Lauria Fabio,Viero Gabriella,Clamer Massimiliano eLife A vast portion of the mammalian genome is transcribed as long non-coding RNAs (lncRNAs) acting in the cytoplasm with largely unknown functions. Surprisingly, lncRNAs have been shown to interact with ribosomes, encode peptides, or act as ribosome sponges. These functions still remain mostly undetected and understudied owing to the lack of efficient tools for genome-wide simultaneous identification of ribosome-associated and peptide-producing lncRNAs. Here, we present AHA-mediated RIBOsome isolation (AHARIBO), a method for the detection of lncRNAs either untranslated, but associated with ribosomes, or encoding small peptides. Using AHARIBO in mouse embryonic stem cells during neuronal differentiation, we isolated ribosome-protected RNA fragments, translated RNAs, and corresponding de novo synthesized peptides. Besides identifying mRNAs under active translation and associated ribosomes, we found and distinguished lncRNAs acting as ribosome sponges or encoding micropeptides, laying the ground for a better functional understanding of hundreds of lncRNAs. 10.7554/eLife.59303
Small Peptide-Protein Interaction Pair for Genetically Encoded, Fixation Compatible Peptide-PAINT. Nano letters Super-resolution microscopy via PAINT has been widely adopted in life sciences to interrogate the nanoscale architecture of many cellular structures. However, obtaining quantitative information in fixed cellular samples remains challenging because control of labeling stoichiometry is hampered in current approaches due to click-chemistry and additional targeting probes. To overcome these challenges, we have identified a small, PDZ-based, peptide-protein interaction pair that is genetically encodable and compatible with super-resolution imaging upon cellular fixation without additional labeling. Stoichiometric labeling control by genetic incorporation of this probe into the cellular vimentin network and mitochondria resulted in super-resolved 3D reconstructions with high specificity and spatial resolution. Further characterization reveals that this peptide-protein interaction is compatible with quantitative PAINT and that its binding kinetics remains unaltered upon fixation. Finally, by fusion of our probe to nanobodies against conventional expression markers, we show that this approach provides a versatile addition to the super-resolution toolbox. 10.1021/acs.nanolett.1c02895
The microprotein encoded by exosomal lncAKR1C2 promotes gastric cancer lymph node metastasis by regulating fatty acid metabolism. Cell death & disease Lymph node metastasis (LNM) is the prominent route of gastric cancer dissemination, and usually leads to tumor progression and a dismal prognosis of gastric cancer. Although exosomal lncRNAs have been reported to be involved in tumor development, whether secreted lncRNAs can encode peptides in recipient cells remains unknown. Here, we identified an exosomal lncRNA (lncAKR1C2) that was clinically correlated with lymph node metastasis in gastric cancer in a VEGFC-independent manner. Exo-lncAKR1C2 secreted from gastric cancer cells was demonstrated to enhance tube formation and migration of lymphatic endothelial cells, and facilitate lymphangiogenesis and lymphatic metastasis in vivo. By comparing the metabolic characteristics of LN metastases and primary focuses, we found that LN metastases of gastric cancer displayed higher lipid metabolic activity. Moreover, exo-lncAKR1C2 encodes a microprotein (pep-AKR1C2) in lymphatic endothelial cells and promotes CPT1A expression by regulating YAP phosphorylation, leading to enhanced fatty acid oxidation (FAO) and ATP production. These findings highlight a novel mechanism of LNM and suggest that the microprotein encoded by exosomal lncAKR1C2 serves as a therapeutic target for advanced gastric cancer. 10.1038/s41419-023-06220-1
Current overview on viroid-host interactions. Adkar-Purushothama Charith Raj,Perreault Jean-Pierre Wiley interdisciplinary reviews. RNA Viroids are one of the most enigmatic highly structured, circular, single-stranded RNA phytopathogens. Although they are not known to code for any peptide, viroids induce visible symptoms in susceptible host plants that resemble those associated with many plant viruses. It is known that viroids induce disease symptoms by direct interaction with host factors; however, the precise mechanism by which this occurs remains poorly understood. Studies on the host's responses to viroid infection, host susceptibility and nonhost resistance have been underway for several years, but much remains to be done in order to fully understand the complex nature of viroid-host interactions. Recent progress using molecular biology techniques combined with computational algorithms, in particular evidence of the role of viroid-derived small RNAs in the RNA silencing pathways of a disease network, has widened the knowledge of viroid pathogenicity. The complexity of viroid-host interactions has been revealed in the past decades to include, but not be limited to, the involvement of host factors, viroid structural complexity, and viroid-induced ribosomal stress, which is further boosted by the discovery of long noncoding RNAs (lncRNAs). In this review, the current understanding of the viroid-host interaction has been summarized with the goal of simplifying the complexity of viroid biology for future research. This article is categorized under: RNA in Disease and Development > RNA in Disease. 10.1002/wrna.1570
Association between lncRNAs in plasma exosomes and diabetic retinopathy. Frontiers in endocrinology Background:Long noncoding RNA (lncRNA) in plasma exosomes is a potential non-invasive diagnostic biomarker for diabetic retinopathy (DR). However, the changes in plasma exosomal lncRNAs and diagnostic relevance in patients with DR patients remain unclear. Methods:A case-control study with type 2 diabetes mellitus (T2DM) and patients with comorbid DR were enrolled, and their clinical information and blood samples were collected. Plasma exosomes were extracted, and the relative expression levels of representative differentially expressed exosomal lncRNAs were determined. A logistic regression model was used to analyze the relationships of DR with relative lncRNA expression and DR-related factors, and receiver operating characteristic (ROC) curve analysis was used to evaluate the value of exosomal lncRNAs for DR diagnosis. Results:Sixty-two patients with T2DM and sixty-two patients with DR were matched by age, sex, and disease duration. The fasting blood glucose concentration, glycosylated hemoglobin level (HbA), and relative expression of the plasma exosomal lncRNA were significantly higher in the DR group than in the T2DM group, whereas the 2-h C-peptide concentration and relative expression of the lncRNAs and were lower in the DR group. After adjusting for relevant confounders, the fasting blood glucose concentration, HbA level, 2-h C-peptide concentration, and relative expression of lncRNA , , and were found to be associated with DR. Both [area under the curve (AUC): 0.658 (0.562-0.754)], [AUC: 0.798 (0.722-0.873)], and [AUC: 0.603 (0.503-0.702)] expression had predictive value for DR diagnosis. The combination of and yielded an AUC of 0.813 (0.740-0.886). In males, the combination of and yielded an AUC of 0.860 (0.780-0.940). Conclusion:The fasting blood glucose concentration, HbA level, and exosomal expression were identified as risk factors for DR, whereas the 2-h C-peptide concentration and exosomal and were identified as protective against DR. The combination of exosomal and had good diagnostic value for DR in the general population and males. More attention should be paid to the role of exosomal expression as a predictive and diagnostic DR biomarker in females. 10.3389/fendo.2022.987488
Shining in the dark: the big world of small peptides in plants. aBIOTECH Small peptides represent a subset of dark matter in plant proteomes. Through differential expression patterns and modes of action, small peptides act as important regulators of plant growth and development. Over the past 20 years, many small peptides have been identified due to technical advances in genome sequencing, bioinformatics, and chemical biology. In this article, we summarize the classification of plant small peptides and experimental strategies used to identify them as well as their potential use in agronomic breeding. We review the biological functions and molecular mechanisms of small peptides in plants, discuss current problems in small peptide research and highlight future research directions in this field. Our review provides crucial insight into small peptides in plants and will contribute to a better understanding of their potential roles in biotechnology and agriculture. 10.1007/s42994-023-00100-0
Small open reading frames in plant research: from prediction to functional characterization. 3 Biotech Gene prediction is a laborious and time-consuming task. The advancement of sequencing technologies and bioinformatics tools, coupled with accelerated rate of ribosome profiling and mass spectrometry development, have made identification of small open reading frames (sORFs) (< 100 codons) in various plant genomes possible. The past 50 years have seen sORFs being isolated from many organisms. However, to date, a comprehensive sORF annotation pipeline is as yet unavailable, hence, addressed in our review. Here, we also provide current information on classification and functions of plant sORFs and their potential applications in crop improvement programs. 10.1007/s13205-022-03147-w
De Novo Designed α-Helical Coiled-Coil Peptides as Scaffolds for Chemical Reactions. Rink W Mathis,Thomas Franziska Chemistry (Weinheim an der Bergstrasse, Germany) Coiled coils (CCs) are well-understood protein-folding motifs. They appear in a variety of oligomer states and as homo- and heteromeric assemblies. This versatility and the general accessibility by de novo design makes them ideal building blocks for synthetic biology. This Minireview highlights the efforts being made in designing small peptide catalysts or reaction templates based on the CC scaffold. The first reports described autocatalysis or mediation of peptide ligation based on CC recognition. Over the years, the designs became more advanced, catalyzing ester hydrolysis, acyl transfer and redox reactions with partial enzyme-like reactivity. Due to the ability to control CC assembly, and, in heterodimeric systems, the association and dissociation, the CC motif has become a common peptide tag in chemical biology. 10.1002/chem.201802849
Neuromedin U: A Small Peptide in the Big World of Cancer. Przygodzka Patrycja,Soboska Kamila,Sochacka Ewelina,Boncela Joanna Cancers Neuromedin U (NMU), a neuropeptide isolated from porcine spinal cord and named because of its activity as a rat uterus smooth muscle contraction inducer, is emerging as a new player in the tumorigenesis and/or metastasis of many types of cancers. Expressed in a variety of tissues, NMU has been shown to possess many important activities in the central nervous system as well as on the periphery. Along with the main structural and functional features of NMU and its currently known receptors, we summarized a growing number of recently published data from different tissues and cells that associate NMU activity with cancer development and progression. We ask if, based on current reports, NMU can be included as a marker of these processes and/or considered as a therapeutic target. 10.3390/cancers11091312
The microproteome of cancer: From invisibility to relevance. Merino-Valverde Iñaki,Greco Emanuela,Abad María Experimental cell research Recent findings have revealed that many genomic regions previously annotated as non-protein coding actually contain small open reading frames, smaller that 300 bp, that are transcribed and translated into evolutionary conserved microproteins. To date, only a small subset of them have been functionally characterized, but they play key functions in fundamental processes such as DNA repair, RNA processing and metabolism regulation. This emergent field seems to hide a new category of molecular regulators with clinical potential. In this review, we focus on its relevance for cancer. Following Hanahan and Weinberg's classification of the hallmarks of cancer, we provide an overview of those microproteins known to be implicated in cancer or those that, based on their function, are likely to play a role in cancer. The resulting picture is that while we are at the very early times of this field, it holds the promise to provide crucial information to understand cancer biology. 10.1016/j.yexcr.2020.111997
Small peptide signaling pathways modulating macronutrient utilization in plants. de Bang Thomas C,Lay Katerina S,Scheible Wolf-Rüdiger,Takahashi Hideki Current opinion in plant biology Root system architecture (RSA) and physiological functions define macronutrient uptake efficiency. Small signaling peptides (SSPs), that act in manners similar to hormones, and their cognate receptors transmit signals both locally and systemically. Several SSPs controlling morphological and physiological traits of roots have been identified to be associated with macronutrient uptake. Recent development in plant genome research has provided an avenue toward systems-based identification and prediction of additional SSPs. This review highlights recent studies on SSP pathways important for optimization of macronutrient uptake and provides new insights into the diversity of SSPs regulated in response to changes in macronutrient availabilities. 10.1016/j.pbi.2017.05.005
Rational Design of Protein-Specific Folding Modifiers. Das Anirban,Yadav Anju,Gupta Mona,R Purushotham,Terse Vishram L,Vishvakarma Vicky,Singh Sameer,Nandi Tathagata,Banerjee Arkadeep,Mandal Kalyaneswar,Gosavi Shachi,Das Ranabir,Ainavarapu Sri Rama Koti,Maiti Sudipta Journal of the American Chemical Society Protein-folding can go wrong and , with significant consequences for the living organism and the pharmaceutical industry, respectively. Here we propose a design principle for small-peptide-based protein-specific folding modifiers. The principle is based on constructing a "xenonucleus", which is a prefolded peptide that mimics the folding nucleus of a protein. Using stopped-flow kinetics, NMR spectroscopy, Förster resonance energy transfer, single-molecule force measurements, and molecular dynamics simulations, we demonstrate that a xenonucleus can make the refolding of ubiquitin faster by 33 ± 5%, while variants of the same peptide have little or no effect. Our approach provides a novel method for constructing specific, genetically encodable folding catalysts for suitable proteins that have a well-defined contiguous folding nucleus. 10.1021/jacs.1c09611
A hidden translatome in tumors-the coding lncRNAs. Science China. Life sciences Long noncoding RNAs (lncRNAs) have been extensively identified in eukaryotic genomes and have been shown to play critical roles in the development of multiple cancers. Through the application and development of ribosome analysis and sequencing technologies, advanced studies have discovered the translation of lncRNAs. Although lncRNAs were originally defined as noncoding RNAs, many lncRNAs actually contain small open reading frames that are translated into peptides. This opens a broad area for the functional investigation of lncRNAs. Here, we introduce prospective methods and databases for screening lncRNAs with functional polypeptides. We also summarize the specific lncRNA-encoded proteins and their molecular mechanisms that promote or inhibit cancerous. Importantly, the role of lncRNA-encoded peptides/proteins holds promise in cancer research, but some potential challenges remain unresolved. This review includes reports on lncRNA-encoded peptides or proteins in cancer, aiming to provide theoretical basis and related references to facilitate the discovery of more functional peptides encoded by lncRNA, and to further develop new anti-cancer therapeutic targets as well as clinical biomarkers of diagnosis and prognosis. 10.1007/s11427-022-2289-6
LncRNAs: key players and novel insights into diabetes mellitus. Oncotarget Long non-coding RNAs (LncRNAs) are a class of endogenous RNA molecules, which have a transcribing length of over 200 nt, lack a complete functional open reading frame (ORF), and rarely encode a functional short peptide. Recent studies have revealed that disruption of LncRNAs levels correlates with several human diseases, including diabetes mellitus (DM), a complex multifactorial metabolic disorder affecting more than 400 million people worldwide. LncRNAs are emerging as pivotal regulators in various biological processes, in the progression of DM and its associated complications, involving pancreatic β-cell disorder, insulin resistance, and epigenetic regulation, . Further investigation into the mechanisms of action of LncRNAs in DM will be of great value in the thorough understanding of pathogenesis. However, prior to successful application of LncRNAs, further search for molecular biomarkers and drug targets to provide a new strategy for DM prevention, early diagnosis, and therapy is warranted. 10.18632/oncotarget.19921
hnRNPK-derived cell-penetratingpeptide inhibits cancer cell survival. Puvvula Pavan Kumar,Buczkowski Stephanie,Moon Anne M Molecular therapy oncolytics hnRNPK is a multifunctional protein that plays an important role in cancer cell proliferation and metastasis via its RNA- and DNA-binding properties. Previously we showed that cell-penetrating peptides derived from the RGG RNA-binding domain of SAFA (hnRNPU) disrupt cancer cell proliferation and survival. Here we explore the efficacy of a peptide derived from the RGG domain of hnRNPK. This peptide acts in a dominant-negative manner on several hnRNPK functions to induce death of multiple types of cancer cells. The peptide phenocopies the effect of hnRNPK knockdown on its mRNA-stability targets such as and and alters the levels and locations of long non-coding RNAs (lncRNAs) and proteins required for nuclear and paraspeckle formation and function. The RGG-derived peptide also decreases euchromatin as evidenced by loss of active marks and polymerase II occupancy. Our findings reveal the potential therapeutic utility of the hnRNPK RGG-derived peptide in a range of cancers. 10.1016/j.omto.2021.10.004
Unannotated microprotein EMBOW regulates the interactome and chromatin and mitotic functions of WDR5. Cell reports The conserved WD40-repeat protein WDR5 interacts with multiple proteins both inside and outside the nucleus. However, it is currently unclear whether and how the distribution of WDR5 between complexes is regulated. Here, we show that an unannotated microprotein EMBOW (endogenous microprotein binder of WDR5) dually encoded in the human SCRIB gene interacts with WDR5 and regulates its binding to multiple interaction partners, including KMT2A and KIF2A. EMBOW is cell cycle regulated, with two expression maxima at late G1 phase and G2/M phase. Loss of EMBOW decreases WDR5 interaction with KIF2A, aberrantly shortens mitotic spindle length, prolongs G2/M phase, and delays cell proliferation. In contrast, loss of EMBOW increases WDR5 interaction with KMT2A, leading to WDR5 binding to off-target genes, erroneously increasing H3K4me3 levels, and activating transcription of these genes. Together, these results implicate EMBOW as a regulator of WDR5 that regulates its interactions and prevents its off-target binding in multiple contexts. 10.1016/j.celrep.2023.113145
Biochemistry and Protein Interactions of the CYREN Microprotein. Biochemistry Over the past decade, advances in genomics have identified thousands of additional protein-coding small open reading frames (smORFs) missed by traditional gene finding approaches. These smORFs encode peptides and small proteins, commonly termed micropeptides or microproteins. Several of these newly discovered microproteins have biological functions and operate through interactions with proteins and protein complexes within the cell. CYREN1 is a characterized microprotein that regulates double-strand break repair in mammalian cells through interaction with Ku70/80 heterodimer. Ku70/80 binds to and stabilizes double-strand breaks and recruits the machinery needed for nonhomologous end join repair. In this study, we examined the biochemical properties of CYREN1 to better understand and explain its cellular protein interactions. Our findings support that CYREN1 is an intrinsically disordered microprotein and this disordered structure allows it to enriches several proteins, including a newly discovered interaction with SF3B1 via a distinct short linear motif (SLiMs) on CYREN1. Since many microproteins are predicted to be disordered, CYREN1 is an exemplar of how microproteins interact with other proteins and reveals an unknown scaffolding function of this microprotein that may link NHEJ and splicing. 10.1021/acs.biochem.3c00397
Epigenetic Connection of the Calcitonin Gene-Related Peptide and Its Potential in Migraine. International journal of molecular sciences The calcitonin gene-related peptide (CGRP) is implicated in the pathogenesis of several pain-related syndromes, including migraine. Targeting CGRP and its receptor by their antagonists and antibodies was a breakthrough in migraine therapy, but the need to improve efficacy and limit the side effects of these drugs justify further studies on the regulation of CGRP in migraine. The expression of the CGRP encoding gene, , is modulated by epigenetic modifications, including the DNA methylation, histone modification, and effects of micro RNAs (miRNAs), circular RNAs, and long-coding RNAs (lncRNAs). On the other hand, CGRP can change the epigenetic profile of neuronal and glial cells. The promoter of the gene has two CpG islands that may be specifically methylated in migraine patients. DNA methylation and lncRNAs were shown to play a role in the cell-specific alternative splicing of the primary transcript. CGRP may be involved in changes in neural cytoarchitecture that are controlled by histone deacetylase 6 (HDAC6) and can be related to migraine. Inhibition of HDAC6 results in reduced cortical-spreading depression and a blockade of the CGRP receptor. CGRP levels are associated with the expression of several miRNAs in plasma, making them useful peripheral markers of migraine. The fundamental role of CGRP in inflammatory pain transmission may be epigenetically regulated. In conclusion, epigenetic connections of CGRP should be further explored for efficient and safe antimigraine therapy. 10.3390/ijms23116151
The TINCR ubiquitin-like microprotein is a tumor suppressor in squamous cell carcinoma. Nature communications The TINCR (Terminal differentiation-Induced Non-Coding RNA) gene is selectively expressed in epithelium tissues and is involved in the control of human epidermal differentiation and wound healing. Despite its initial report as a long non-coding RNA, the TINCR locus codes for a highly conserved ubiquitin-like microprotein associated with keratinocyte differentiation. Here we report the identification of TINCR as a tumor suppressor in squamous cell carcinoma (SCC). TINCR is upregulated by UV-induced DNA damage in a TP53-dependent manner in human keratinocytes. Decreased TINCR protein expression is prevalently found in skin and head and neck squamous cell tumors and TINCR expression suppresses the growth of SCC cells in vitro and in vivo. Consistently, Tincr knockout mice show accelerated tumor development following UVB skin carcinogenesis and increased penetrance of invasive SCCs. Finally, genetic analyses identify loss-of-function mutations and deletions encompassing the TINCR gene in SCC clinical samples supporting a tumor suppressor role in human cancer. Altogether, these results demonstrate a role for TINCR as protein coding tumor suppressor gene recurrently lost in squamous cell carcinomas. 10.1038/s41467-023-36713-8
MicroProteins: Dynamic and accurate regulation of protein activity. Journal of integrative plant biology Proteins usually assemble oligomers or high-order complexes to increase their efficiency and specificity in biological processes. The dynamic equilibrium of complex formation and disruption imposes reversible regulation of protein function. MicroProteins are small, single-domain proteins that directly bind target protein complexes and disrupt their assembly. Growing evidence shows that microProteins are efficient regulators of protein activity at the post-translational level. In the last few decades, thousands of plant microProteins have been predicted by computational approaches, but only a few have been experimentally validated. Recent studies highlighted the mechanistic working modes of newly-identified microProteins in Arabidopsis and other plant species. Here, we review characterized microProteins, including their biological roles, regulatory targets, and modes of action. In particular, we focus on microProtein-directed allosteric modulation of key components in light signaling pathways, and we summarize the biogenesis and evolutionary trajectory of known microProteins in plants. Understanding the regulatory mechanisms of microProteins is an important step towards potential utilization of microProteins as versatile biotechnological tools in crop bioengineering. 10.1111/jipb.13229
Plant microProteins: Small but powerful modulators of plant development. iScience MicroProteins (miPs) are small and single-domain containing proteins of less than 20 kDa. This domain allows microProteins to interact with compatible domains of evolutionary-related proteins and fine-tuning the key physiological pathways in several organisms. Since the first report of a microProtein in mice, numerous microProteins have been identified in plants by computational approaches. However, only a few candidates have been functionally characterized, primarily in Arabidopsis. The recent success of synthetic microProteins in modulating physiological activities in crops makes these proteins interesting candidates for crop engineering. Here, we comprehensively summarise the synthesis, mode of action, and functional roles of microProteins in plants. We also discuss different approaches used to identify plant microProteins. Additionally, we discuss novel approaches to design synthetic microProteins that can be used to target proteins regulating plant growth and development. We finally highlight the prospects and challenges of utilizing microProteins in future crop improvement programs. 10.1016/j.isci.2022.105400
Exploring the Peptide Potential of Genomes. Methods in molecular biology (Clifton, N.J.) Recent studies attribute a central role to the noncoding genome in the emergence of novel genes. The widespread transcription of noncoding regions and the pervasive translation of the resulting RNAs offer to the organisms a vast reservoir of novel peptides. Although the majority of these peptides are anticipated as deleterious or neutral, and thereby expected to be degraded right away or short-lived in evolutionary history, some of them can confer an advantage to the organism. The latter can be further subjected to natural selection and be established as novel genes. In any case, characterizing the structural properties of these pervasively translated peptides is crucial to understand (1) their impact on the cell and (2) how some of these peptides, derived from presumed noncoding regions, can give rise to structured and functional de novo proteins. Therefore, we present a protocol that aims to explore the potential of a genome to produce novel peptides. It consists in annotating all the open reading frames (ORFs) of a genome (i.e., coding and noncoding ones) and characterizing the fold potential and other structural properties of their corresponding potential peptides. Here, we apply our protocol to a small genome and show how to apply it to very large genomes. Finally, we present a case study which aims to probe the fold potential of a set of 721 translated ORFs in mouse lncRNAs, identified with ribosome profiling experiments. Interestingly, we show that the distribution of their fold potential is different from that of the nontranslated lncRNAs and more generally from the other noncoding ORFs of the mouse. 10.1007/978-1-0716-1855-4_3
LncRNA CTBP1-DT-encoded microprotein DDUP sustains DNA damage response signalling to trigger dual DNA repair mechanisms. Nucleic acids research Sustaining DNA damage response (DDR) signalling via retention of DDR factors at damaged sites is important for transmitting damage-sensing and repair signals. Herein, we found that DNA damage provoked the association of ribosomes with IRES region in lncRNA CTBP1-DT, which overcame the negative effect of upstream open reading frames (uORFs), and elicited the novel microprotein DNA damage-upregulated protein (DDUP) translation via a cap-independent translation mechanism. Activated ATR kinase-mediated phosphorylation of DDUP induced a drastic 'dense-to-loose' conformational change, which sustained the RAD18/RAD51C and RAD18/PCNA complex at damaged sites and initiated RAD51C-mediated homologous recombination and PCNA-mediated post-replication repair mechanisms. Importantly, treatment with ATR inhibitor abolished the effect of DDUP on chromatin retention of RAD51C and PCNA, thereby leading to hypersensitivity of cancer cells to DNA-damaging chemotherapeutics. Taken together, our results uncover a plausible mechanism underlying the DDR sustaining and might represent an attractive therapeutic strategy in improvement of DNA damage-based anticancer therapies. 10.1093/nar/gkac611
Recent Advances in Small Peptides of Marine Origin in Cancer Therapy. Zhang Qi-Ting,Liu Ze-Dong,Wang Ze,Wang Tao,Wang Nan,Wang Ning,Zhang Bin,Zhao Yu-Fen Marine drugs Cancer is one of the leading causes of death in the world, and antineoplastic drug research continues to be a major field in medicine development. The marine milieu has thousands of biological species that are a valuable source of novel functional proteins and peptides, which have been used in the treatment of many diseases, including cancer. In contrast with proteins and polypeptides, small peptides (with a molecular weight of less than 1000 Da) have overwhelming advantages, such as preferential and fast absorption, which can decrease the burden on human gastrointestinal function. Besides, these peptides are only connected by a few peptide bonds, and their small molecular weight makes it easy to modify and synthesize them. Specifically, small peptides can deliver nutrients and drugs to cells and tissues in the body. These characteristics make them stand out in relation to targeted drug therapy. Nowadays, the anticancer mechanisms of the small marine peptides are still largely not well understood; however, several marine peptides have been applied in preclinical treatment. This paper highlights the anticancer linear and cyclic small peptides in marine resources and presents a review of peptides and the derivatives and their mechanisms. 10.3390/md19020115
Insights into lncRNAs in Alzheimer's disease mechanisms. RNA biology Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common dementia among the elderly. The pathophysiology of AD is characterized by two hallmarks: amyloid plaques, produced by amyloid β (Aβ) aggregation, and neurofibrillary tangle (NFT), produced by accumulation of phosphorylated tau. The regulatory roles of non-coding RNAs (ncRNAs), particularly long noncoding RNAs (lncRNAs), have been widely recognized in gene expression at the transcriptional and posttranscriptional levels. Mounting evidence shows that lncRNAs are aberrantly expressed in AD progression. Here, we review the lncRNAs that implicated in the regulation of Aβ peptide, tau, inflammation, cell death, and other aspects which are the main mechanisms of AD pathology. We also discuss the possible clinical or therapeutic utility of lncRNA detection or targeting to help diagnose or possibly combat AD. 10.1080/15476286.2020.1788848
CXCR7 Targeting and Its Major Disease Relevance. Wang Chuan,Chen Weilin,Shen Jianzhong Frontiers in pharmacology Chemokine receptors are the target of small peptide chemokines. They play various important roles in physiological and pathological processes. CXCR7, later renamed ACKR3, is a non-classical seven transmembrane-spanning receptor whose function as a signaling or non-signaling scavenger/decoy receptor is currently under debate. Even for cell signaling mechanisms, there has been inconsistency on whether CXCR7 couples to G-proteins or β-arrestins. Several reasons may contribute to this uncertainty or controversy. In one hand, it has been neglected that CXCR7 has more than five natural ligands and unfortunately, most of the prior research only studied SDF-1 (CXCL12) and/or I-TAC (CXCL11); on the other hand, there are mounting evidence supporting ligand and tissue bias for receptor signaling, but limited such information is available for CXCR7. In this review we focus on summarizing the endogenous and exogenous ligands of CXCR7, the main diseases related to CXCR7 and the biased signaling events happening on CXCR7. These three aspects of CXCR7 pharmacologic properties may explain why the contradicting opinions of whether CXCR7 is a signaling or non-signaling receptor exist. Further, potential new direction and perspective for the study of CXCR7 biology and pharmacology are highlighted. 10.3389/fphar.2018.00641
MECHANISMS IN ENDOCRINOLOGY: The physiology of neuronostatin. Andersen Mads R,Suppli Malte P,Bagger Jonatan I,Christensen Mikkel B,Yosten Gina L C,Knop Filip K,Lund Asger European journal of endocrinology In 2008, the first evidence of a new hormone called neuronostatin was published. The hormone was discovered using a bioinformatic method and found to originate from the same preprohormone as somatostatin. This small peptide hormone of 13 amino acids and a C-terminal amidation was soon found to exert pleiotropic physiological effects. In animal studies, neuronostatin has been shown to reduce food intake and delay gastric emptying and gastrointestinal transit. Furthermore, neuronostatin has been shown to affect glucose metabolism by increasing glucagon secretion during situations when glucose concentrations are low. Additionally, neuronostatin has been shown to affect neural tissue and cardiomyocytes by suppressing cardiac contractility. The effects of neuronostatin have not yet been delineated in humans, but if the effects found in animal studies translate to humans it could position neuronostatin as a promising target in the treatment of obesity, hypertension and diabetes. In this review, we describe the discovery of neuronostatin and the current understanding of its physiological role and potential therapeutic applicability. 10.1530/EJE-21-0347
Structure, Regulation, and Function of Linear and Circular Long Non-Coding RNAs. Qin Tao,Li Juan,Zhang Ke-Qin Frontiers in genetics Long non-coding RNAs (lncRNAs), including linear lncRNAs and circular RNAs (circRNAs), exhibit a surprising range of structures. Linear lncRNAs and circRNAs are generated by different pathways. Linear lncRNAs perform functions that depend on their specific sequences, transcription, and DNA elements of their gene loci. In some cases, linear lncRNAs contain a short open reading frame encoding a peptide. circRNAs are covalently closed RNAs with tissue-specific and cell-specific expression patterns that have recently been extensively investigated. Pioneering work focusing on their biogenesis and functional characterization indicates that circRNAs regulate cell development via multiple mechanisms and play critical roles in the immune system. Furthermore, circRNAs in exosomes function on target cells. As with linear lncRNAs, specific circRNAs can also be translated. In this review, we summarize current understanding and highlight the diverse structure, regulation, and function of linear lncRNAs and circRNAs. 10.3389/fgene.2020.00150
The hidden world of membrane microproteins. Makarewich Catherine A Experimental cell research Proteins are critical components of biological membranes and play key roles in many essential cellular processes. Membrane proteins are a structurally and functionally diverse family of proteins that have recently expanded to include a number of newly discovered tiny proteins called microproteins, or micropeptides. These microproteins are generated from small open reading frames, which produce protein products that are less than 100 amino acids in length. While not all microproteins are membrane proteins, this review will focus specifically on this subclass to highlight some of the important biological activities that have been ascribed to these molecules and to emphasize their promise as exciting new players in membrane biology. 10.1016/j.yexcr.2020.111853
The hunt for sORFs: A multidisciplinary strategy. Peeters Marlies K R,Menschaert Gerben Experimental cell research Growing evidence illustrates the shortcomings on the current understanding of the full complexity of the proteome. Previously overlooked small open reading frames (sORFs) and their encoded microproteins have filled important gaps, exerting their function as biologically relevant regulators. The characterization of the full small proteome has potential applications in many fields. Continuous development of techniques and tools led to an improved sORF discovery, where these can originate from bioinformatics analyses, from sequencing routines or proteomics approaches. In this mini review, we discuss the ongoing trends in the three fields and suggest some strategies for further characterization of high potential candidates. 10.1016/j.yexcr.2020.111923
Mapping subcellular localizations of unannotated microproteins and alternative proteins with MicroID. Molecular cell Proteogenomic identification of translated small open reading frames has revealed thousands of previously unannotated, largely uncharacterized microproteins, or polypeptides of less than 100 amino acids, and alternative proteins (alt-proteins) that are co-encoded with canonical proteins and are often larger. The subcellular localizations of microproteins and alt-proteins are generally unknown but can have significant implications for their functions. Proximity biotinylation is an attractive approach to define the protein composition of subcellular compartments in cells and in animals. Here, we developed a high-throughput technology to map unannotated microproteins and alt-proteins to subcellular localizations by proximity biotinylation with TurboID (MicroID). More than 150 microproteins and alt-proteins are associated with subnuclear organelles. One alt-protein, alt-LAMA3, localizes to the nucleolus and functions in pre-rRNA transcription. We applied MicroID in a mouse model, validating expression of a conserved nuclear microprotein, and establishing MicroID for discovery of microproteins and alt-proteins in vivo. 10.1016/j.molcel.2022.06.035
Functional Peptides Encoded by Long Non-Coding RNAs in Gastrointestinal Cancer. Chen Yao,Long Weili,Yang Liqiong,Zhao Yueshui,Wu Xu,Li Mingxing,Du Fukuan,Chen Yu,Yang Zhihui,Wen Qinglian,Yi Tao,Xiao Zhangang,Shen Jing Frontiers in oncology Gastrointestinal cancer is by far the most common malignancy and the most common cause of cancer-related deaths worldwide. Recent studies have shown that long non-coding RNAs (lncRNAs) play an important role in the epigenetic regulation of cancer cells and regulate tumor progression by affecting chromatin modifications, gene transcription, translation, and sponge to miRNAs. In particular, lncRNA has recently been found to possess open reading frame (ORF), which can encode functional small peptides or proteins. These peptides interact with its targets to regulate transcription or the signal axis, thus promoting or inhibiting the occurrence and development of tumors. In this review, we summarize the involvement of lncRNAs and the function of lncRNAs encoded small peptides in gastrointestinal cancer. 10.3389/fonc.2021.777374
Kidney-Related Function of Mitochondrial Protein Mitoregulin. International journal of molecular sciences A small protein, Mitoregulin (Mtln), localizes in mitochondria and contributes to oxidative phosphorylation and fatty acid metabolism. knockout mice develop obesity on a high-fat diet, demonstrating elevated cardiolipin damage and suboptimal creatine kinase oligomerization in muscle tissue. Kidneys heavily depend on the oxidative phosphorylation in mitochondria. Here we report kidney-related phenotypes in aged knockout mice. Similar to knockout mice muscle mitochondria, those of the kidney demonstrate a decreased respiratory complex I activity and excessive cardiolipin damage. Aged male mice carrying knockout demonstrated an increased frequency of renal proximal tubules' degeneration. At the same time, a decreased glomerular filtration rate has been more frequently detected in aged female mice devoid of Mtln. An amount of Mtln partner protein, Cyb5r3, is drastically decreased in the kidneys of knockout mice. 10.3390/ijms24109106
Casting CRISPR-Cas13d to fish for microprotein functions in animal development. iScience Protein coding genes were originally identified with sequence-based definitions that included a 100-codon cutoff to avoid annotating irrelevant open reading frames. However, many active proteins contain less than 100 amino acids. Indeed, functional genetics, ribosome profiling, and proteomic profiling have identified many short, translated open reading frames, including those with biologically active peptide products (microproteins). Yet, functions for most of these peptide products remain unknown. Because microproteins often act as key signals or fine-tune processes, animal development has already revealed functions for a handful of microproteins and provides an ideal context to uncover additional microprotein functions. However, many mRNAs during early development are maternally provided and hinder targeted mutagenesis approaches to characterize developmental microprotein functions. The recently established, RNA-targeting CRISPR-Cas13d system in zebrafish overcomes this barrier and produces potent knockdown of targeted mRNA, including maternally provided mRNA, and enables flexible, efficient interrogation of microprotein functions in animal development. 10.1016/j.isci.2022.105547
Progress in long non-coding RNAs in animals. Lu Chang,Huang Yin-Hua Yi chuan = Hereditas Long non-coding RNAs (lncRNAs) are important transcripts that are more than 200 nucleotides in length, and distribute extensively in animal and plant genomes. Accumulated studies demonstrate that lncRNAs play critical roles in biological processes related to embryogenesis, muscle development, lipid deposition and immune responses. They assist protein complexes in translocating to appropriate locations and participate in regulating gene activation and inactivation. Recently, rapid progress of lncRNA research is emerging, largely due to molecular biological technologies and information developed in the human genome project and the Encyclopedia of DNA Elements (ENCODE) project. For example, a dwarf open reading frame (DWORF) encoded by an annotated lncRNA was reported to activate the SERCA pump. Moreover, small regulatory polypeptide of amino acid response (SPAR) encoded by lncRNA LINC00961 was found to regulate muscle regeneration. These new results have revealed a novel model that lncRNA regulates biological processes using its small peptide product. In this review, we summarize the characteristics, databases, biological functions and molecular regulatory models, as well as research interests of lncRNAs in the future. 10.16288/j.yczz.17-120
MIEF1 Microprotein Regulates Mitochondrial Translation. Rathore Annie,Chu Qian,Tan Dan,Martinez Thomas F,Donaldson Cynthia J,Diedrich Jolene K,Yates John R,Saghatelian Alan Biochemistry Recent technological advances led to the discovery of hundreds to thousands of peptides and small proteins (microproteins) encoded by small open reading frames (smORFs). Characterization of new microproteins demonstrates their role in fundamental biological processes and highlights the value in discovering and characterizing more microproteins. The elucidation of microprotein-protein interactions (MPIs) is useful for determining the biochemical and cellular roles of microproteins. In this study, we characterize the protein interaction partners of mitochondrial elongation factor 1 microprotein (MIEF1-MP) using a proximity labeling strategy that relies on APEX2. MIEF1-MP localizes to the mitochondrial matrix where it interacts with the mitochondrial ribosome (mitoribosome). Functional studies demonstrate that MIEF1-MP regulates mitochondrial translation via its binding to the mitoribosome. Loss of MIEF1-MP decreases the mitochondrial translation rate, while an elevated level of MIEF1-MP increases the translation rate. The identification of MIEF1-MP reveals a new gene involved in this process. 10.1021/acs.biochem.8b00726
Revisiting sORFs: overcoming challenges to identify and characterize functional microproteins. Schlesinger Dörte,Elsässer Simon J The FEBS journal Short ORFs (sORFs), that is, occurrences of a start and stop codon within 100 codons or less, can be found in organisms of all domains of life, outnumbering annotated protein-coding ORFs by orders of magnitude. Even though functional proteins smaller than 100 amino acids are known, the coding potential of sORFs has often been overlooked, as it is not trivial to predict and test for functionality within the large number of sORFs. Recent advances in ribosome profiling and mass spectrometry approaches, together with refined bioinformatic predictions, have enabled a huge leap forward in this field and identified thousands of likely coding sORFs. A relatively low number of small proteins or microproteins produced from these sORFs have been characterized so far on the molecular, structural, and/or mechanistic level. These however display versatile and, in some cases, essential cellular functions, allowing for the exciting possibility that many more, previously unknown small proteins might be encoded in the genome, waiting to be discovered. This review will give an overview of the steadily growing microprotein field, focusing on eukaryotic small proteins. We will discuss emerging themes in the molecular action of microproteins, as well as advances and challenges in microprotein identification and characterization. 10.1111/febs.15769
Microproteins: Overlooked regulators of physiology and disease. iScience Ongoing efforts to generate a complete and accurate annotation of the genome have revealed a significant blind spot for small proteins (<100 amino acids) originating from short open reading frames (sORFs). The recent discovery of numerous sORF-encoded proteins, termed microproteins, that play diverse roles in critical cellular processes has ignited the field of microprotein biology. Large-scale efforts are currently underway to identify sORF-encoded microproteins in diverse cell-types and tissues and specialized methods and tools have been developed to aid in their discovery, validation, and functional characterization. Microproteins that have been identified thus far play important roles in fundamental processes including ion transport, oxidative phosphorylation, and stress signaling. In this review, we discuss the optimized tools available for microprotein discovery and validation, summarize the biological functions of numerous microproteins, outline the promise for developing microproteins as therapeutic targets, and look forward to the future of the field of microprotein biology. 10.1016/j.isci.2023.106781
Overlapping mechanisms of lncRNA and expanded microsatellite RNA. Wiley interdisciplinary reviews. RNA RNA has major regulatory roles in a wide range of biological processes and a surge of RNA research has led to the classification of numerous functional RNA species. One example is long noncoding RNAs (lncRNAs) that are structurally complex transcripts >200 nucleotides (nt) in length and lacking a canonical open reading frame (ORF). Despite a general lack of sequence conservation and low expression levels, many lncRNAs have been shown to have functionality in diverse biological processes as well as in mechanisms of disease. In parallel with the growing understanding of lncRNA functions, there is a growing subset of microsatellite expansion disorders in which the primary mechanism of pathogenesis is an RNA gain of function arising from RNA transcripts from the mutant allele. Microsatellite expansion disorders are caused by an expansion of short (3-10 nt) repeats located within coding genes. Expanded repeat-containing RNA mediates toxicity through multiple mechanisms, the details of which remain only partially understood. The purpose of this review is to highlight the links between functional mechanisms of lncRNAs and the potential pathogenic mechanisms of expanded microsatellite RNA. These shared mechanisms include protein sequestration, peptide translation, micro-RNA (miRNA) processing, and miRNA sequestration. Recognizing the parallels between the normal functions of lncRNAs and the negative impact of expanded microsatellite RNA on biological processes can provide reciprocal understanding to the roles of both RNA species. This article is categorized under: RNA Interactions with Proteins and Other Molecules > Protein-RNA Interactions: Functional Implications RNA in Disease and Development > RNA in Disease. 10.1002/wrna.1634
Microbial production of small peptide: pathway engineering and synthetic biology. Microbial biotechnology Small peptides are a group of natural products with low molecular weights and complex structures. The diverse structures of small peptides endow them with broad bioactivities and suggest their potential therapeutic use in the medical field. The remaining challenge is methods to address the main limitations, namely (i) the low amount of available small peptides from natural sources, and (ii) complex processes required for traditional chemical synthesis. Therefore, harnessing microbial cells as workhorse appears to be a promising approach to synthesize these bioactive peptides. As an emerging engineering technology, synthetic biology aims to create standard, well-characterized and controllable synthetic systems for the biosynthesis of natural products. In this review, we describe the recent developments in the microbial production of small peptides. More importantly, synthetic biology approaches are considered for the production of small peptides, with an emphasis on chassis cells, the evolution of biosynthetic pathways, strain improvements and fermentation. 10.1111/1751-7915.13743
LINC00493-encoded microprotein SMIM26 exerts anti-metastatic activity in renal cell carcinoma. EMBO reports Human microproteins encoded by long non-coding RNAs (lncRNA) have been increasingly discovered, however, complete functional characterization of these emerging proteins is scattered. Here, we show that LINC00493-encoded SMIM26, an understudied microprotein localized in mitochondria, is tendentiously downregulated in clear cell renal cell carcinoma (ccRCC) and correlated with poor overall survival. LINC00493 is recognized by RNA-binding protein PABPC4 and transferred to ribosomes for translation of a 95-amino-acid protein SMIM26. SMIM26, but not LINC00493, suppresses ccRCC growth and metastatic lung colonization by interacting with acylglycerol kinase (AGK) and glutathione transport regulator SLC25A11 via its N-terminus. This interaction increases the mitochondrial localization of AGK and subsequently inhibits AGK-mediated AKT phosphorylation. Moreover, the formation of the SMIM26-AGK-SCL25A11 complex maintains mitochondrial glutathione import and respiratory efficiency, which is abrogated by AGK overexpression or SLC25A11 knockdown. This study functionally characterizes the LINC00493-encoded microprotein SMIM26 and establishes its anti-metastatic role in ccRCC, and therefore illuminates the importance of hidden proteins in human cancers. 10.15252/embr.202256282
Association between obesity and iron deficiency (Review). Alshwaiyat Naseem Mohammad,Ahmad Aryati,Wan Hassan Wan Mohd Razin,Al-Jamal Hamid Ali Nagi Experimental and therapeutic medicine Obesity is a risk factor for several comorbidities and complications, including iron deficiency anemia. Iron deficiency anemia is a serious global public health problem, with a worldwide prevalence. The high prevalence of obesity in combination with iron deficiency incidence observed in different age and sex categories suggests an association between obesity and iron status. Obesity may disrupt iron homeostasis, resulting in iron deficiency anemia. The association between obesity and iron deficiency may be due to increased hepcidin levels mediated by chronic inflammation. Hepcidin is a small peptide hormone that functions as a negative regulator of intestinal iron absorption. Significant body weight loss in overweight and obese individuals decreases chronic inflammation and serum hepcidin levels, resulting in improved iron status due to increased iron absorption. However, further randomized controlled trials are required to confirm this effect. 10.3892/etm.2021.10703
Small Open Reading Frames, How to Find Them and Determine Their Function. Kute Preeti Madhav,Soukarieh Omar,Tjeldnes Håkon,Trégouët David-Alexandre,Valen Eivind Frontiers in genetics Advances in genomics and molecular biology have revealed an abundance of small open reading frames (sORFs) across all types of transcripts. While these sORFs are often assumed to be non-functional, many have been implicated in physiological functions and a significant number of sORFs have been described in human diseases. Thus, sORFs may represent a hidden repository of functional elements that could serve as therapeutic targets. Unlike protein-coding genes, it is not necessarily the encoded peptide of an sORF that enacts its function, sometimes simply the act of translating an sORF might have a regulatory role. Indeed, the most studied sORFs are located in the 5'UTRs of coding transcripts and can have a regulatory impact on the translation of the downstream protein-coding sequence. However, sORFs have also been abundantly identified in non-coding RNAs including lncRNAs, circular RNAs and ribosomal RNAs suggesting that sORFs may be diverse in function. Of the many different experimental methods used to discover sORFs, the most commonly used are ribosome profiling and mass spectrometry. These can confirm interactions between transcripts and ribosomes and the production of a peptide, respectively. Extensions to ribosome profiling, which also capture scanning ribosomes, have further made it possible to see how sORFs impact the translation initiation of mRNAs. While high-throughput techniques have made the identification of sORFs less difficult, defining their function, if any, is typically more challenging. Together, the abundance and potential function of many of these sORFs argues for the necessity of including sORFs in gene annotations and systematically characterizing these to understand their potential functional roles. In this review, we will focus on the high-throughput methods used in the detection and characterization of sORFs and discuss techniques for validation and functional characterization. 10.3389/fgene.2021.796060
The neurobehavioral implications of the brain and microbiota interaction. Onaolapo Olakunle James,Onaolapo Adejoke Yetunde,Olowe Adekunle Olugbenga Frontiers in bioscience (Landmark edition) In the past, microorganisms were not considered to be particularly important in brain development and functioning. However, recent evidence shows the existence of a bidirectional, and possibly multidimensional relationship between the body microbiota and the brain. The microbiota influence brain behavior in health or disease, by utilizing endocrine, neurocrine and immunologic signaling pathways. Also, the chemical mediators involved range from known neurotransmitters to small peptide molecules. Here, we discuss the evidence that currently exists in experimental animals and/or humans in support of the existence of a relationship involving the skin/gut microbiome, the brain, and behavior; and the mechanisms involved in such interactions. The implications of such interactions for shifts in behaviors, and the pathogenesis of behavioral and neurodegenerative disorders are also discussed. Finally, the possible clinical applications of deliberate manipulations of the microbiota composition and density for the management or prevention of behavioral and neurodegenerative disorders is discussed. 10.2741/4810
Small Bioactive Peptides for Biomaterials Design and Therapeutics. Hamley I W Chemical reviews This review is aimed to provide a concise yet extensive survey of key short bioactive peptide sequences for a range of applications ranging from biomaterials development to peptides with therapeutic uses. The following are considered: cell adhesion motifs, structural peptides, cell-penetrating and tumor-homing peptides, antimicrobial peptides, peptide hormones, growth factors and matrix metalloprotease substrates, neuropeptides, amyloid peptides, antioxidant peptides, peptide affinity tags, anticancer peptides, and others. This review provides a convenient resource, summarizing a broad range of important sequences with great utility as a resource concerning both small peptide drugs and also novel biofunctional peptide-based materials. 10.1021/acs.chemrev.7b00522
Sumoylation in Cellular Senescence and Aging. Gong L,Sun Q,Li D W-C Current molecular medicine Sumoylation is a reversible post-translational modification that conjugates small peptide SUMO (small ubiquitin-like modifier) to a target protein. Global protein sumoylation and expression of components in sumoylation pathway were recently found to be altered in the process of organismal aging. In addition, key factors controlling cellular senescence are known to be sumoylated. This review will summarize current information on the function of sumoylation in cellular senescence and aging. 10.2174/1566524016666161223104915
Alzheimer's Disease Model System Using Drosophila. Tsuda Leo,Lim Young-Mi Advances in experimental medicine and biology Alzheimer's disease (AD) is the most epidemic neuronal dysfunctions among elderly people. It is accompanied by neuronal disorders along with learning and memory defects, as well as massive neurodegeneration phenotype. The presence of intracellular neurofibrillary tangles (NFTs) and extracellular amyloid plaques, called senile plaques (SPs), and brain atrophy are typically observed in the brains of AD patients. It has been over 20 years since the discovery that small peptide, called beta-amyloid (Aβ), has pivotal role for the disease formation. Since then, a variety of drugs have been developed to cure AD; however, there is currently no effective drug for the disorder. This therapeutic void reflects lacks of ideal model system, which can evaluate the progression of AD in a short period. Recently, large numbers of AD model system have been established using Drosophila melanogaster by overproducing Aβ molecules in the brain. These systems successfully reflect some of the symptoms along with AD. In this review, we would like to point out "pros and cons" of Drosophila AD models. 10.1007/978-981-13-0529-0_3
Sensing the allosteric force. Nature communications Allosteric regulation is an innate control in most metabolic and signalling cascades that enables living organisms to adapt to the changing environment by tuning the affinity and regulating the activity of target proteins. For a microscopic understanding of this process, a protein system has been designed in such a way that allosteric communication between the binding and allosteric site can be observed in both directions. To that end, an azobenzene-derived photoswitch has been linked to the α3-helix of the PDZ3 domain, arguably the smallest allosteric protein with a clearly identifiable binding and allosteric site. Photo-induced trans-to-cis isomerisation of the photoswitch increases the binding affinity of a small peptide ligand to the protein up to 120-fold, depending on temperature. At the same time, ligand binding speeds up the thermal cis-to-trans back-isomerisation rate of the photoswitch. Based on the energetics of the four states of the system (cis vs trans and ligand-bound vs free), the concept of an allosteric force is introduced, which can be used to drive chemical reactions. 10.1038/s41467-020-19689-7
Peptides as epigenetic modulators: therapeutic implications. Janssens Yorick,Wynendaele Evelien,Vanden Berghe Wim,De Spiegeleer Bart Clinical epigenetics Peptides originating from different sources (endogenous, food derived, environmental, and synthetic) are able to influence different aspects of epigenetic regulation. Endogenous short peptides, resulting from proteolytic cleavage of proteins or upon translation of non-annotated out of frame transcripts, can block DNA methylation and hereby regulate gene expression. Peptides entering the body by digestion of food-related proteins can modulate DNA methylation and/or histone acetylation while environmental peptides, synthesized by bacteria, fungi, and marine sponges, mainly inhibit histone deacetylation. In addition, synthetic peptides that reverse or inhibit different epigenetic modifications of both histones and the DNA can be developed as well. Next to these DNA and histone modifications, peptides can also influence the expression of non-coding RNAs such as lncRNAs and the maturation of miRNAs.Seen the advantages over small molecules, the development of peptide therapeutics is an interesting approach to treat diseases with a strong epigenetic basis like cancer and Alzheimer's disease. To date, only a limited number of drugs with a proven epigenetic mechanism of action have been approved by the FDA of which two (romidepsin and nesiritide) are peptides. A large knowledge gap concerning epigenetic effects of peptides is present, and this class of molecules deserves more attention in the development as epigenetic modulators. In addition, none of the currently approved peptide drugs are under investigation for their potential effects on epigenetics, hampering drug repositioning of these peptides to other indications with an epigenetic etiology. 10.1186/s13148-019-0700-7
The Tumorigenic Effect of lncRNA AFAP1-AS1 is Mediated by Translated Peptide ATMLP Under the Control of m A Methylation. Advanced science (Weinheim, Baden-Wurttemberg, Germany) Long noncoding RNAs (lncRNAs) in eukaryotic transcripts have long been believed to regulate various aspects of cellular processes, including carcinogenesis. Herein, it is found that lncRNA AFAP1-AS1 encodes a conserved 90-amino acid peptide located on mitochondria, named lncRNA AFAP1-AS1 translated mitochondrial-localized peptide (ATMLP), and it is not the lncRNA but the peptide that promotes the malignancy of nonsmall cell lung cancer (NSCLC). As the tumor progresses, the serum level of ATMLP increases. NSCLC patients with high levels of ATMLP display poorer prognosis. Translation of ATMLP is controlled by m A methylation at the 1313 adenine locus of AFAP1-AS1. Mechanistically, ATMLP binds to the 4-nitrophenylphosphatase domain and non-neuronal SNAP25-like protein homolog 1 (NIPSNAP1) and inhibits its transport from the inner to the outer mitochondrial membrane, which antagonizes the NIPSNAP1-mediated regulation of cell autolysosome formation. The findings uncover a complex regulatory mechanism of NSCLC malignancy orchestrated by a peptide encoded by a lncRNA. A comprehensive judgment of the application prospects of ATMLP as an early diagnostic biomarker for NSCLC is also made. 10.1002/advs.202300314
LncRNA-Encoded Peptide: Functions and Predicting Methods. Xing Jiani,Liu Haizhou,Jiang Wei,Wang Lihong Frontiers in oncology Long non-coding RNA (lncRNA) was originally defined as the representative of the non-coding RNAs and unable to encode. However, recent reports suggest that some lncRNAs actually contain open reading frames that encode peptides. These coding products play important roles in the pathogenesis of many diseases. Here, we summarize the regulatory pathways of mammalian lncRNA-encoded peptides in influencing muscle function, mRNA stability, gene expression, and so on. We also address the promoting and inhibiting functions of the peptides in different cancers and other diseases. Then we introduce the computational predicting methods and data resources to predict the coding ability of lncRNA. The intention of this review is to provide references for further coding research and contribute to reveal the potential prospects for targeted tumor therapy. 10.3389/fonc.2020.622294
Ghrelin and cancer progression. Lin Tsung-Chieh,Hsiao Michael Biochimica et biophysica acta. Reviews on cancer Ghrelin is a small peptide with 28 amino acids, and has been characterized as the ligand of the growth hormone secretagogue receptor (GHSR). In addition to its original function in stimulating pituitary growth hormone release, ghrelin is multifunctional and plays a role in the regulation of energy balance, gastric acid release, appetite, insulin secretion, gastric motility and the turnover of gastric and intestinal mucosa. The discovery of ghrelin and GHSR expression beyond normal tissues suggests its role other than physiological function. Emerging evidences have revealed ghrelin's function in regulating several processes related to cancer progression, especially in metastasis and proliferation. We further show the relative GHRL and GHSR expression in pan-cancers from The Cancer Genome Atlas (TCGA), suggesting the potential pathological role of the axis in cancers. This review focuses on ghrelin's biological function in cancer progression, and reveals its clinical significance especially the impact on cancer patient outcome. 10.1016/j.bbcan.2017.02.002
N4-acetylcytidine modification of lncRNA CTC-490G23.2 promotes cancer metastasis through interacting with PTBP1 to increase CD44 alternative splicing. Oncogene Although N4-acetylcytidine (ac4C) modification affects the stability and translation of mRNA, it is unknown whether it exists in noncoding RNAs, and its biological function is unclear. Here, nucleotide-resolution method for profiling CTC-490G23.2 ac4C sites and gain- and loss-of-function experiments revealed that N-acetyltransferase 10 (NAT10) is responsible for ac4C modification of long noncoding RNAs (lncRNAs). NAT10-mediated ac4C modification leads to the stabilization and overexpression of lncRNA CTC-490G23.2 in primary esophageal squamous cell carcinoma (ESCC) and its further upregulation in metastatic tissues. CTC-490G23.2 significantly promotes cancer invasion and metastasis in vitro and in vivo. Mechanistically, CTC-490G23.2 acts as a scaffold to increase the binding of CD44 pre-mRNA to polypyrimidine tract-binding protein 1 (PTBP1), resulting in a oncogenic splicing switch from the standard isoform CD44s to the variant isoform CD44v(8-10). CD44v(8-10), but not CD44s, binds to and increases the protein stability of vimentin. Expression levels of CTC-490G23.2 and CD44v(8-10) can predict poor prognosis in cancer patients. Furthermore, the antisense oligonucleotide (ASO)/SV40-LAH4-L1 peptide self-assembled nanocomplexes targeting CTC490G23.2 exerts a significantly suppressive effect on cancer metastasis. The outcome of this study will provide new mechanistic insight into the ac4C modification of lncRNAs and useful clues for the development of novel systemic therapies and prognostic biomarkers. 10.1038/s41388-023-02628-3
Chemotropism and Cell-Cell Fusion in Fungi. Microbiology and molecular biology reviews : MMBR Fungi exhibit an enormous variety of morphologies, including yeast colonies, hyphal mycelia, and elaborate fruiting bodies. This diversity arises through a combination of polar growth, cell division, and cell fusion. Because fungal cells are nonmotile and surrounded by a protective cell wall that is essential for cell integrity, potential fusion partners must grow toward each other until they touch and then degrade the intervening cell walls without impacting cell integrity. Here, we review recent progress on understanding how fungi overcome these challenges. Extracellular chemoattractants, including small peptide pheromones, mediate communication between potential fusion partners, promoting the local activation of core cell polarity regulators to orient polar growth and cell wall degradation. However, in crowded environments, pheromone gradients can be complex and potentially confusing, raising the question of how cells can effectively find their partners. Recent findings suggest that the cell polarity circuit exhibits searching behavior that can respond to pheromone cues through a remarkably flexible and effective strategy called exploratory polarization. 10.1128/mmbr.00165-21
pH regulates peptide-receptor perception. Trends in plant science Diverse plant small peptides are perceived by their corresponding receptors to mediate local or long-distance intercellular communications in various developmental and adaptive programs; notably, the mechanisms of peptide-receptor perception remain largely unrevealed. Two reports (Liu et al.; Diaz-Ardila et al.) shed light on how pH regulates peptide-receptor perception. 10.1016/j.tplants.2023.04.015
Mining for Small Translated ORFs. Chugunova Anastasia,Navalayeu Tsimafei,Dontsova Olga,Sergiev Petr Journal of proteome research Peptides encoded by short open reading frames (sORFs) are usually defined as peptides ≤100 aa long. Usually sORFs were ignored by automatic genome annotation programs due to the high probability of false discovery. However, improved computational tools along with a high-throughput RIBO-seq approach identified a myriad of translated sORFs. Their importance becomes evident as we are gaining experimental validation of their diverse cellular functions. This Review examines various computational and experimental approaches of sORFs identification as well as provides the summary of our current knowledge of their functional roles in cells. 10.1021/acs.jproteome.7b00707
Long Noncoding RNAs as Therapeutic Targets. Advances in experimental medicine and biology Long noncoding RNAs (lncRNAs) have emerged as critical regulators of cellular functions including maintenance of cellular homeostasis as well as the onset and progression of disease. LncRNAs often exhibit cell-, tissue-, and disease-specific expression patterns, making them desirable therapeutic targets. LncRNAs are commonly targeted using oligonucleotide therapeutics, and advances in oligonucleotide chemistry including C2 ribose sugar modifications such as 2'-fluoro, 2'-O-methyl, and 2-O-methoxyethyl modifications; 2'4'-constrained nucleotides such as locked nucleic acids and constrained 2'-O-ethyl (cEt) nucleotides; and phosphorothioate bonds have dramatically improved efficacy of oligonucleotide therapies. Novel delivery platforms such as viral vectors and nanoparticles have also improved pharmacokinetic properties of oligonucleotides targeting lncRNAs. Accumulating pre-clinical studies have utilized these strategies to therapeutically target lncRNAs and alter progression of many different disease states including Snhg12 and Chast in cardiovascular disease, Mirt2 and HOTTIP in sepsis and autoimmune disease, and Malat1 and HOXB-AS3 in cancer. Emerging oligonucleotide conjugation methods including the use of peptide nucleic acids hold promise to facilitate targeting to specific tissue types. Here, we review recent advances in lncRNA therapeutics and provide examples of how lncRNAs have been successfully targeted in pre-clinical models of disease. Finally, we detail remaining challenges facing the lncRNA field and how advances in delivery platforms and oligonucleotide chemistry might help overcome these barriers to catalyze the translation of pre-clinical studies to successful pharmaceutical development. 10.1007/978-3-030-92034-0_9
pTINCR microprotein promotes epithelial differentiation and suppresses tumor growth through CDC42 SUMOylation and activation. Nature communications The human transcriptome contains thousands of small open reading frames (sORFs) that encode microproteins whose functions remain largely unexplored. Here, we show that TINCR lncRNA encodes pTINCR, an evolutionary conserved ubiquitin-like protein (UBL) expressed in many epithelia and upregulated upon differentiation and under cellular stress. By gain- and loss-of-function studies, we demonstrate that pTINCR is a key inducer of epithelial differentiation in vitro and in vivo. Interestingly, low expression of TINCR associates with worse prognosis in several epithelial cancers, and pTINCR overexpression reduces malignancy in patient-derived xenografts. At the molecular level, pTINCR binds to SUMO through its SUMO interacting motif (SIM) and to CDC42, a Rho-GTPase critical for actin cytoskeleton remodeling and epithelial differentiation. Moreover, pTINCR increases CDC42 SUMOylation and promotes its activation, triggering a pro-differentiation cascade. Our findings suggest that the microproteome is a source of new regulators of cell identity relevant for cancer. 10.1038/s41467-022-34529-6
Cellular senescence in hepatocellular carcinoma induced by a long non-coding RNA-encoded peptide PINT87aa by blocking FOXM1-mediated . Theranostics Recently, long non-coding RNAs (lncRNAs), known to be involved in human cancer progression, have been shown to encode peptides with biological functions, but the role of lncRNA-encoded peptides in cellular senescence is largely unexplored. We previously reported the tumor-suppressive role of PINT87aa, a peptide encoded by the long intergenic non-protein coding RNA, p53 induced transcript ( Here, we investigated PINT87aa's role in hepatocellular carcinoma (HCC) cellular senescence. We examined PINT87aa and truncated PINT87aa functions by monitoring cell proliferation and performed flow cytometry, senescence-associated β-galactosidase staining, JC-1 staining indicative of mitochondrial membrane potential, the ratio of the overlapping area of light chain 3 beta (LC3B) and mitochondrial probes and the ratio of lysosomal associated membrane protein 1 (LAMP1) overlapping with cytochrome c oxidase subunit 4I1 (COXIV) denoting mitophagy. PINT87aa and truncated PINT87aa functions were verified by subcutaneously transplanted tumors in nude mice. The possible binding between PINT87aa and forkhead box M1 (FOXM1) was predicted through structural analysis and verified by co-immunoprecipitation and immunofluorescence co-localization. Rescue experiments were performed following FOXM1 overexpression. Further, chromatin immunoprecipitation, polymerase chain reaction, and dual-luciferase reporter gene assay were conducted to validate FOXM1 binding to the () promoter. PINT87aa was significantly increased in the hydrogen peroxide-induced HCC cell senescence model. Overexpression of PINT87aa induced growth inhibition, cellular senescence, and decreased mitophagy and . In contrast, FOXM1 gain-of-function could partially reduce the proportion of senescent HCC cells and enhance mitophagy. PINT87aa overexpression did not affect the expression of FOXM1 itself but reduced that of its target genes involved in cell cycle and proliferation, especially which was involved in mitophagy and transcribed by FOXM1. Structural analysis indicated that PINT87aa could bind to the DNA-binding domain of FOXM1, which was confirmed by co-immunoprecipitation and immunofluorescence co-localization. Furthermore, we demonstrated that the 2 to 39 amino acid truncated form of the peptide exerted effects similarly to the full form. Our study established the role of PINT87aa as a novel biomarker and a key regulator of cellular senescence in HCC and identified PINT87aa as a potential therapeutic target for HCC. 10.7150/thno.55672
Ghrelin and vascular protection. Pearson James T,Shirai Mikiyasu,Sukumaran Vijayakumar,Du Cheng-Kun,Tsuchimochi Hirotsugu,Sonobe Takashi,Waddingham Mark T,Katare Rajesh,Schwenke Daryl O Vascular biology (Bristol, England) Ghrelin is a small peptide with important roles in the regulation of appetite, gut motility, glucose homeostasis as well as cardiovascular protection. This review highlights the role that acyl ghrelin plays in maintaining normal endothelial function by maintaining the balance of vasodilator-vasoconstrictor factors, inhibiting inflammatory cytokine production and immune cell recruitment to sites of vascular injury and by promoting angiogenesis. 10.1530/VB-19-0024
Endothelin Signaling in Bone. Kristianto Jasmin,Johnson Michael G,Afzal Rafia,Blank Robert D Endocrinology and metabolism clinics of North America The endothelin (ET) system includes 3 small peptide hormones and a pair of G-protein-coupled receptors. This review first outlines the ET signaling pathway and ET metabolism. Next, it summarizes the role of ET1 signaling in craniofacial development. Then, it discusses observations relating ET signaling to osteoblastic and other osteosclerotic processes in cancer. Finally, it describes recent work in our laboratory that points to endothelin signaling as an upstream mediator of WNT signaling, promoting bone matrix synthesis and mineralization. It concludes with a statement of some remaining gaps in knowledge and proposals for future research. 10.1016/j.ecl.2016.09.014
Mitochondrial DNA variation in Alzheimer's disease reveals a unique microprotein called SHMOOSE. Molecular psychiatry Mitochondrial DNA variants have previously associated with disease, but the underlying mechanisms have been largely elusive. Here, we report that mitochondrial SNP rs2853499 associated with Alzheimer's disease (AD), neuroimaging, and transcriptomics. We mapped rs2853499 to a novel mitochondrial small open reading frame called SHMOOSE with microprotein encoding potential. Indeed, we detected two unique SHMOOSE-derived peptide fragments in mitochondria by using mass spectrometry-the first unique mass spectrometry-based detection of a mitochondrial-encoded microprotein to date. Furthermore, cerebrospinal fluid (CSF) SHMOOSE levels in humans correlated with age, CSF tau, and brain white matter volume. We followed up on these genetic and biochemical findings by carrying out a series of functional experiments. SHMOOSE acted on the brain following intracerebroventricular administration, differentiated mitochondrial gene expression in multiple models, localized to mitochondria, bound the inner mitochondrial membrane protein mitofilin, and boosted mitochondrial oxygen consumption. Altogether, SHMOOSE has vast implications for the fields of neurobiology, Alzheimer's disease, and microproteins. 10.1038/s41380-022-01769-3
Artificial Intracellular Filaments. Cell reports. Physical science Intracellular protein filaments are ubiquitous for cellular functions, but forming bona fide biomimetic intracellular filaments of small molecules in living cells remains elusive. Here, we report the formation of self-limiting intracellular filaments of a small peptide via enzymatic morphological transition of a phosphorylated and trimethylated heterochiral tetrapeptide. Enzymatic dephosphorylation reduces repulsive intermolecular electrostatic interactions and converts the peptidic nanoparticles into filaments, which exhibit distinct types of cross-β structures with either C7 or C2 symmetries, with the hydrophilic C-terminal residues at the periphery of the helix. Macromolecular crowding promotes the peptide filaments to form bundles, which extend from the plasma membrane to nuclear membrane and hardly interact with endogenous components, including cytoskeletons. Stereochemistry and post-translational modification (PTM) of peptides are critical for generating the intracellular bundles. This work may offer a way to gain lost functions or to provide molecular insights for understanding normal and aberrant intracellular filaments. 10.1016/j.xcrp.2020.100085
Microproteins-Discovery, structure, and function. Proteomics Advances in proteogenomic technologies have revealed hundreds to thousands of translated small open reading frames (sORFs) that encode microproteins in genomes across evolutionary space. While many microproteins have now been shown to play critical roles in biology and human disease, a majority of recently identified microproteins have little or no experimental evidence regarding their functionality. Computational tools have some limitations for analysis of short, poorly conserved microprotein sequences, so additional approaches are needed to determine the role of each member of this recently discovered polypeptide class. A currently underexplored avenue in the study of microproteins is structure prediction and determination, which delivers a depth of functional information. In this review, we provide a brief overview of microprotein discovery methods, then examine examples of microprotein structures (and, conversely, intrinsic disorder) that have been experimentally determined using crystallography, cryo-electron microscopy, and NMR, which provide insight into their molecular functions and mechanisms. Additionally, we discuss examples of predicted microprotein structures that have provided insight or context regarding their function. Analysis of microprotein structure at the angstrom level, and confirmation of predicted structures, therefore, has potential to identify translated microproteins that are of biological importance and to provide molecular mechanism for their in vivo roles. 10.1002/pmic.202100211
Biological pincer complexes. Nevarez Jorge,Turmo Aiko,Hu Jian,Hausinger Robert P ChemCatChem At least two types of pincer complexes are known to exist in biology. A metal-pyrroloquinolone quinone (PQQ) cofactor was first identified in bacterial methanol dehydrogenase, and later also found in selected short-chain alcohol dehydrogenases of other microorganisms. The PQQ-associated metal can be calcium, magnesium, or a rare earth element depending on the enzyme sequence. Synthesis of this organic ligand requires a series of accessory proteins acting on a small peptide, PqqA. Binding of metal to PQQ yields an ONO-type pincer complex. More recently, a nickel-pincer nucleotide (NPN) cofactor was discovered in lactate racemase, LarA. This cofactor derives from nicotinic acid adenine dinucleotide via action of a carboxylase/hydrolase, sulfur transferase, and nickel insertase, resulting in an SCS-type pincer complex. The NPN cofactor likely occurs in selected other racemases and epimerases of bacteria, archaea, and a few eukaryotes. 10.1002/cctc.202000575
Peptide SMIM30 promotes HCC development by inducing SRC/YES1 membrane anchoring and MAPK pathway activation. Pang Yanan,Liu Zhiyong,Han Huan,Wang Beilei,Li Wei,Mao Chuanbin,Liu Shanrong Journal of hepatology BACKGROUND & AIMS:Growing evidence shows that some non-coding RNAs (ncRNAs) contain small open reading frames (smORFs) that are translated into short peptides. Herein, we aimed to determine where and how these short peptides might promote hepatocellular carcinoma (HCC) development. METHODS:We performed an RNA-immunoprecipitation followed by high-throughput sequencing (RIP-seq) assay with an antibody against ribosomal protein S6 (RPS6) on 4 cancer cell lines. Focusing on 1 long non-coding RNA (lncRNA), LINC00998, we used qPCR and public databases to evaluate its expression level in patients with HCC. Special vectors were constructed to confirm its coding potential. We also explored the function and mechanism of LINC00998-encoded peptide in tumor growth and metastasis. RESULTS:We discovered that many lncRNAs bind to RPS6 in cancer cells. One of these lncRNAs, LINC00998, encoded a small endogenous peptide, termed SMIM30. SMIM30, rather than the RNA itself, promoted HCC tumorigenesis by modulating cell proliferation and migration, and its level was correlated with poor survival in patients with HCC. Furthermore, SMIM30 was transcribed by c-Myc and then drove the membrane anchoring of the non-receptor tyrosine kinases SRC/YES1. Moreover, the downstream MAPK signaling pathway was activated by SRC/YES1. CONCLUSIONS:Our results not only unravel a new mechanism of HCC tumorigenesis promoted by ncRNA-encoded peptides, but also suggest that these peptides can serve as a new target for HCC cancer therapy and a new biomarker for HCC diagnosis and prognosis. LAY SUMMARY:Very little is known about how peptides activate signaling pathways that play a crucial role in diseases such as cancer. Specifically, we reported on a conserved peptide encoded by LINC00998, SMIM30. This peptide promoted the tumorigenesis of hepatocellular carcinoma (HCC) by modulating cell proliferation and migration. Of note, it bound the non-receptor tyrosine kinases, SRC/YES1, to drive their membrane anchoring and phosphorylation, activating the downstream MAPK signaling pathway. Our work not only unravels a new mechanism of HCC tumorigenesis promoted by peptides, but also demonstrates how the peptide works to activate a signaling pathway. 10.1016/j.jhep.2020.05.028
A Peptide Encoded by a Putative lncRNA HOXB-AS3 Suppresses Colon Cancer Growth. Huang Jin-Zhou,Chen Min,Chen De,Gao Xing-Cheng,Zhu Song,Huang Hongyang,Hu Min,Zhu Huifang,Yan Guang-Rong Molecular cell A substantial fraction of eukaryotic transcripts are considered long non-coding RNAs (lncRNAs), which regulate various hallmarks of cancer. Here, we discovered that the lncRNA HOXB-AS3 encodes a conserved 53-aa peptide. The HOXB-AS3 peptide, not lncRNA, suppresses colon cancer (CRC) growth. Mechanistically, the HOXB-AS3 peptide competitively binds to the ariginine residues in RGG motif of hnRNP A1 and antagonizes the hnRNP A1-mediated regulation of pyruvate kinase M (PKM) splicing by blocking the binding of the ariginine residues in RGG motif of hnRNP A1 to the sequences flanking PKM exon 9, ensuring the formation of lower PKM2 and suppressing glucose metabolism reprogramming. CRC patients with low levels of HOXB-AS3 peptide have poorer prognoses. Our study indicates that the loss of HOXB-AS3 peptide is a critical oncogenic event in CRC metabolic reprogramming. Our findings uncover a complex regulatory mechanism of cancer metabolism reprogramming orchestrated by a peptide encoded by an lncRNA. 10.1016/j.molcel.2017.09.015
Evolutionary origins and interactomes of human, young microproteins and small peptides translated from short open reading frames. Molecular cell All species continuously evolve short open reading frames (sORFs) that can be templated for protein synthesis and may provide raw materials for evolutionary adaptation. We analyzed the evolutionary origins of 7,264 recently cataloged human sORFs and found that most were evolutionarily young and had emerged de novo. We additionally identified 221 previously missed sORFs potentially translated into peptides of up to 15 amino acids-all of which are smaller than the smallest human microprotein annotated to date. To investigate the bioactivity of sORF-encoded small peptides and young microproteins, we subjected 266 candidates to a mass-spectrometry-based interactome screen with motif resolution. Based on these interactomes and additional cellular assays, we can associate several candidates with mRNA splicing, translational regulation, and endocytosis. Our work provides insights into the evolutionary origins and interaction potential of young and small proteins, thereby helping to elucidate this underexplored territory of the human proteome. 10.1016/j.molcel.2023.01.023
Plant Protein -Arabinosylation. Petersen Bent Larsen,MacAlister Cora A,Ulvskov Peter Frontiers in plant science A wide range of proteins with diverse functions in development, defense, and stress responses are -arabinosylated at hydroxyprolines (Hyps) within distinct amino acid motifs of continuous stretches of Hyps, as found in the structural cell wall extensins, or at non-continuous Hyps as, for example, found in small peptide hormones and a variety of plasma membrane proteins involved in signaling. Plant -glycosylation relies on hydroxylation of Prolines to Hyps in the protein backbone, mediated by prolyl-4-hydroxylase (P4H) which is followed by -glycosylation of the Hyp C-OH group by either galactosyltransferases (GalTs) or arabinofuranosyltranferases (AraTs) yielding either Hyp-galactosylation or Hyp-arabinosylation. A subset of the P4H enzymes with putative preference to hydroxylation of continuous prolines and presumably all AraT enzymes needed for synthesis of the substituted arabinose chains of one to four arabinose units, have been identified and functionally characterized. Truncated root-hair phenotype is one common denominator of mutants of Hyp formation and Hyp-arabinosylation glycogenes, which act on diverse groups of -glycosylated proteins, e.g., the small peptide hormones and cell wall extensins. Dissection of different substrate derived effects may not be regularly feasible and thus complicate translation from genotype to phenotype. Recently, lack of proper arabinosylation on arabinosylated proteins has been shown to influence their transport/fate in the secretory pathway, hinting to an additional layer of functionality of -arabinosylation. Here, we provide an update on the prevalence and types of -arabinosylated proteins and the enzymatic machinery responsible for their modifications. 10.3389/fpls.2021.645219
Altered blood gene expression in the obesity-related type 2 diabetes cluster may be causally involved in lipid metabolism: a Mendelian randomisation study. Diabetologia AIMS/HYPOTHESIS:The aim of this study was to identify differentially expressed long non-coding RNAs (lncRNAs) and mRNAs in whole blood of people with type 2 diabetes across five different clusters: severe insulin-deficient diabetes (SIDD), severe insulin-resistant diabetes (SIRD), mild obesity-related diabetes (MOD), mild diabetes (MD) and mild diabetes with high HDL-cholesterol (MDH). This was to increase our understanding of different molecular mechanisms underlying the five putative clusters of type 2 diabetes. METHODS:Participants in the Hoorn Diabetes Care System (DCS) cohort were clustered based on age, BMI, HbA, C-peptide and HDL-cholesterol. Whole blood RNA-seq was used to identify differentially expressed lncRNAs and mRNAs in a cluster compared with all others. Differentially expressed genes were validated in the Innovative Medicines Initiative DIabetes REsearCh on patient straTification (IMI DIRECT) study. Expression quantitative trait loci (eQTLs) for differentially expressed RNAs were obtained from a publicly available dataset. To estimate the causal effects of RNAs on traits, a two-sample Mendelian randomisation analysis was performed using public genome-wide association study (GWAS) data. RESULTS:Eleven lncRNAs and 175 mRNAs were differentially expressed in the MOD cluster, the lncRNA AL354696.2 was upregulated in the SIDD cluster and GPR15 mRNA was downregulated in the MDH cluster. mRNAs and lncRNAs that were differentially expressed in the MOD cluster were correlated among each other. Six lncRNAs and 120 mRNAs validated in the IMI DIRECT study. Using two-sample Mendelian randomisation, we found 52 mRNAs to have a causal effect on anthropometric traits (n=23) and lipid metabolism traits (n=10). GPR146 showed a causal effect on plasma HDL-cholesterol levels (p = 2×10), without evidence for reverse causality. CONCLUSIONS/INTERPRETATION:Multiple lncRNAs and mRNAs were found to be differentially expressed among clusters and particularly in the MOD cluster. mRNAs in the MOD cluster showed a possible causal effect on anthropometric traits, lipid metabolism traits and blood cell fractions. Together, our results show that individuals in the MOD cluster show aberrant RNA expression of genes that have a suggested causal role on multiple diabetes-relevant traits. 10.1007/s00125-023-05886-8
Micropeptide ASAP encoded by LINC00467 promotes colorectal cancer progression by directly modulating ATP synthase activity. Ge Qiwei,Jia Dingjiacheng,Cen Dong,Qi Yadong,Shi Chengyu,Li Junhong,Sang Lingjie,Yang Luo-Jia,He Jiamin,Lin Aifu,Chen Shujie,Wang Liangjing The Journal of clinical investigation Emerging evidence has shown that open reading frames inside long noncoding RNAs (lncRNAs) could encode micropeptides. However, their roles in cellular energy metabolism and tumor progression remain largely unknown. Here, we identified a 94 amino acid-length micropeptide encoded by lncRNA LINC00467 in colorectal cancer. We also characterized its conservation across higher mammals, localization to mitochondria, and the concerted local functions. This peptide enhanced the ATP synthase construction by interacting with the subunits α and γ (ATP5A and ATP5C), increased ATP synthase activity and mitochondrial oxygen consumption rate, and thereby promoted colorectal cancer cell proliferation. Hence, this micropeptide was termed ATP synthase-associated peptide (ASAP). Furthermore, loss of ASAP suppressed patient-derived xenograft growth with attenuated ATP synthase activity and mitochondrial ATP production. Clinically, high expression of ASAP and LINC00467 predicted poor prognosis of colorectal cancer patients. Taken together, our findings revealed a colorectal cancer-associated micropeptide as a vital player in mitochondrial metabolism and provided a therapeutic target for colorectal cancer. 10.1172/JCI152911
Breast Cancer: Current Molecular Therapeutic Targets and New Players. Nagini Siddavaram Anti-cancer agents in medicinal chemistry Breast cancer is the most common cancer and the most frequent cause of cancer death among women worldwide. Breast cancer is a complex, heterogeneous disease classified into hormone-receptor-positive, human epidermal growth factor receptor-2 overexpressing (HER2+) and triple-negative breast cancer (TNBC) based on histological features. Endocrine therapy, the mainstay of treatment for hormone-responsive breast cancer involves use of selective estrogen receptor modulators (SERMs), selective estrogen receptor downregulators (SERDs) and aromatase inhibitors (AIs). Agents that target estrogen receptor (ER) and HER2 such as tamoxifen and trastuzumab have been the most extensively used therapeutics for breast cancer. Crosstalk between ER and other signalling networks as well as epigenetic mechanisms have been envisaged to contribute to endocrine therapy resistance. TNBC, a complex, heterogeneous, aggressive form of breast cancer in which the cells do not express ER, progesterone receptor or HER2 is refractory to therapy. Several molecular targets are being explored to target TNBC including androgen receptor, epidermal growth factor receptor (EGFR), poly(ADP-ribose) polymerase (PARP), and vascular endothelial growth factor (VEGF). Receptors, protein tyrosine kinases, phosphatases, proteases, PI3K/Akt signalling pathway, microRNAs (miRs) and long noncoding RNAs (lncRNAs) are potential therapeutic targets. miR-based therapeutic approaches include inhibition of oncomiRs by antisense oligonucleotides, restoration of tumour suppressors using miR mimics, and chemical modification of miRs. The lnRNAs HOTAIR, SPRY4-IT1, GAS5, and PANDAR, new players in tumour development and prognosis may have theranostic applications in breast cancer. Several novel classes of mechanism-based drugs have been designed and synthesised for treatment of breast cancer. Integration of nucleic acid sequencing studies with mass spectrometry-based peptide sequencing and posttranslational modifications as well as rational drug design will provide a more comprehensive understanding of the pathophysiology of breast cancer and help in evolving therapeutic strategies. 10.2174/1871520616666160502122724
Mitochondria-derived peptides in aging and healthspan. The Journal of clinical investigation The mechanisms that explain mitochondrial dysfunction in aging and healthspan continue to be studied, but one element has been unexplored: microproteins. Small open reading frames in circular mitochondria DNA can encode multiple microproteins, called mitochondria-derived peptides (MDPs). Currently, eight MDPs have been published: humanin, MOTS-c, and SHLPs 1-6. This Review describes recent advances in microprotein discovery with a focus on MDPs. It discusses what is currently known about MDPs in aging and how this new understanding could add to the way we understand age-related diseases including type 2 diabetes, cancer, and neurodegenerative diseases at the genomic, proteomic, and drug-development levels. 10.1172/JCI158449
The small peptide world in long noncoding RNAs. Choi Seo-Won,Kim Hyun-Woo,Nam Jin-Wu Briefings in bioinformatics Long noncoding RNAs (lncRNAs) are a group of transcripts that are longer than 200 nucleotides (nt) without coding potential. Over the past decade, tens of thousands of novel lncRNAs have been annotated in animal and plant genomes because of advanced high-throughput RNA sequencing technologies and with the aid of coding transcript classifiers. Further, a considerable number of reports have revealed the existence of stable, functional small peptides (also known as micropeptides), translated from lncRNAs. In this review, we discuss the methods of lncRNA classification, the investigations regarding their coding potential and the functional significance of the peptides they encode. 10.1093/bib/bby055
Long non-coding RNAs: From disease code to drug role. Chen Yuanyuan,Li Zhaojun,Chen Xiaoguang,Zhang Sen Acta pharmaceutica Sinica. B Enormous studies have corroborated that long non-coding RNAs (lncRNAs) extensively participate in crucial physiological processes such as metabolism and immunity, and are closely related to the occurrence and development of tumors, cardiovascular diseases, nervous system disorders, nephropathy, and other diseases. The application of lncRNAs as biomarkers or intervention targets can provide new insights into the diagnosis and treatment of diseases. This paper has focused on the emerging research into lncRNAs as pharmacological targets and has reviewed the transition of lncRNAs from the role of disease coding to acting as drug candidates, including the current status and progress in preclinical research. Cutting-edge strategies for lncRNA modulation have been summarized, including the sources of lncRNA-related drugs, such as genetic technology and small-molecule compounds, and related delivery methods. The current progress of clinical trials of lncRNA-targeting drugs is also discussed. This information will form a latest updated reference for research and development of lncRNA-based drugs. 10.1016/j.apsb.2020.10.001