The Zinc-dependent HDACs: Non-histone Substrates and Catalytic Deacylation Beyond Deacetylation.
Mini reviews in medicinal chemistry
Protein lysine side chain N(epsilon)-acylation and -deacylation play an important regulatory role in both epigenetic and non-epigenetic processes via a structural and functional regulation of histone and non-histone proteins. The enzymes catalyzing deacylation were traditionally termed as the histone deacetylases (HDACs) since histone proteins were the first substrates identified and the deacetylation was the first type of deacylation identified. However, it has now been known that, besides the seven sirtuins (i.e. SIRT1-7, the β-nicotinamide adenine dinucleotide (β-NAD+)-dependent class III HDACs), several of the other eleven members of the mammalian HDAC family (i.e. HDAC1-11, the zinc-dependent classes I, II, and IV HDACs) have been found to also accept nonhistone proteins as native substrates and to also catalyze the removal of the acyl groups other than acetyl, such as formyl, crotonyl, and myristoyl. In this mini-review, I will first integrate the current literature coverage on the non-histone substrates and the catalytic deacylation (beyond deacetylation) of the zinc-dependent HDACs, which will be followed by an address on the functional interrogation and pharmacological exploitation (inhibitor design) of the zinc-dependent HDAC-catalyzed deacylation (beyond deacetylation).
10.2174/1389557522666220330144151
SIRT6 inhibits hypoxia-induced pulmonary arterial smooth muscle cells proliferation via HIF-1α/PDK4 signaling.
Life sciences
SIRT6 is an NAD-dependent protein that plays a vital role in regulating the cell proliferation, differentiation and apoptosis. Abnormal proliferation of pulmonary artery smooth muscle cells (PASMCs) in peripheral vascular is one of the major pathological findings of pulmonary vascular remodeling in pulmonary arterial hypertension (PAH). However, whether SIRT6 is involved in hypoxia-induced proliferation of PASMCs and its possible mechanisms remain unknown. In the present study, we found that the expression of SIRT6 was decreased in both hypoxia-induced PAH rats model and HPASMCs. Hypoxia promoted the proliferation of HPASMCs in a time-dependent manner, inhibited the activity of caspase-3 and the production of PDH, increased the activity of LDH, ROS level, mitochondrial membrane potential(MMP) and the expression of HIF-1α and PDK4, which induced glycolysis. SIRT6 over-expression could inhibit the proliferation of HPASMCs and increase the apoptosis rate, impelled the retardation of cell cycle in phase G1. Meanwhile, SIRT6 over-expression reduced LDH activity, the levels of ROS and MMP, which simultaneously increased the production of PDH, the expression of HIF-1α, PDK4, Cyclin D1 and PCNA in hypoxia-induced HPASMCs. Moreover, SIRT6 over-expression inhibited the transcriptional activation of HIF-1α/PDK4 signaling. In addition, SIRT6 knockdown with SIRT6 siRNA exhibited the same effect as hypoxia. Together, our results indicated that SIRT6 was participant in regulating hypoxia-induced imbalance of proliferation and apoptosis of HPASMCs, which was associated with the activation of HIF-1α/PDK4 signaling pathway. Targeting at SIRT6 gene and regulating the downstream metabolism signaling pathway may be a novel strategy for the treatment of hypoxia-induced PAH.
10.1016/j.lfs.2022.121192
Overexpression of SLC25A51 promotes hepatocellular carcinoma progression by driving aerobic glycolysis through activation of SIRT5.
Bai Lu,Yang Zhao-Xu,Ma Peng-Fei,Liu Jian-Shan,Wang De-Sheng,Yu Heng-Chao
Free radical biology & medicine
Solute carrier family 25 member 20 (SLC25A51) is a newly identified mammalian mitochondrial NAD transporter. However, the clinicopathological and biological significance of SLC25A51 in human cancers, including hepatocellular carcinoma (HCC), remains unclear. The aim of this study was to define the role of SLC25A51 in HCC progression. Here we demonstrate that SLC25A51 is significantly overexpressed in human HCC specimens and cell lines, caused by, at least in partial, the decrease of miR-212-3p. SLC25A51 overexpression is positively correlated with the clinicopathological characteristics of vascular invasion and tumor diameter, as well as poor survival in patients with HCC. Knockdown of SLC25A51 attenuated, while overexpression of SLC25A51 enhanced the growth and metastasis of HCC cells both in vitro and in vivo. Mechanistically, glucose metabolism reprogramming from oxidative phosphorylation to glycolysis by activation of mitochondrial sirtuin 5 (SIRT5) was found to contribute to the promotion of growth and metastasis by SLC25A51 in HCC cells. Together, these findings reveal important roles of SLC25A51 in HCC tumorigenesis and suggest SLC25A51 as a promising prognostic marker and therapeutic target for treating HCC.
10.1016/j.freeradbiomed.2022.02.014
miR-146a impedes the anti-aging effect of AMPK via NAMPT suppression and NAD/SIRT inactivation.
Signal transduction and targeted therapy
Nicotinamide adenine dinucleotide (NAD) is indispensable for the anti-aging activity of the sirtuin (SIRT) family enzymes. AMP-activated protein kinase (AMPK) upregulates NAD synthesis and SIRT activity in a nicotinamide phosphoribosyltransferase (NAMPT)-dependent manner. However, the molecular mechanisms that affect AMPK-driven NAMPT expression and NAD/SIRT activation remain unclear. In this study, we tried to identify senescence-associated microRNAs (miRNAs) that negatively regulate the cascade linking AMPK and NAMPT expression. miRNA-screening experiments showed that the expression of miR-146a increased in senescent cells but decreased following AMPK activation. Additionally, miR-146a overexpression weakened the metformin-mediated upregulation of NAMPT expression, NAD synthesis, SIRT activity, and senescence protection, whereas treatment with the miR-146a inhibitor reversed this effect. Importantly, these findings were observed both in vitro and in vivo. Mechanistically, miR-146a directly targeted the 3'-UTR of Nampt mRNA to reduce the expression of NAMPT. AMPK activators metformin and 5-aminoimidazole-4-carboxamide (AICAR) hindered miR-146a expression at the transcriptional level by promoting IκB kinase (IKK) phosphorylation to attenuate nuclear factor-kappaB (NF-κB) activity. These findings identified a novel cascade that negatively regulates the NAD/SIRT pathway by suppressing miR-146a-mediated NAMPT downregulation. Furthermore, our results showed that miR-146a impedes the anti-aging effect of AMPK. This mutual inhibitory relationship between miR-146a and AMPK enriches our understanding of the molecular connections between AMPK and SIRT and provides new insight into miRNA-mediated NAD/SIRT regulation and an intervention point for the prevention of aging and age-related diseases.
10.1038/s41392-022-00886-3
SIRT2 negatively regulates the cGAS-STING pathway by deacetylating G3BP1.
EMBO reports
SIRT2, a cytoplasmic member of the Sirtuin family, has important roles in immunity and inflammation. However, its function in regulating the response to DNA virus infection remains elusive. Here, we find that SIRT2 is a unique regulator among the Sirtuin family that negatively modulates the cGAS-STING-signaling pathway. SIRT2 is down-regulated after Herpes simplex virus-1 (HSV-1) infection, and SIRT2 deficiency markedly elevates the expression levels of type I interferon (IFN). SIRT2 inhibits the DNA binding ability and droplet formation of cGAS by interacting with and deacetylating G3BP1 at K257, K276, and K376, leading to the disassembly of the cGAS-G3BP1 complex, which is critical for cGAS activation. Administration of AGK2, a selective SIRT2 inhibitor, protects mice from HSV-1 infection and increases the expression of IFN and IFN-stimulated genes. Our study shows that SIRT2 negatively regulates cGAS activation through G3BP1 deacetylation, suggesting a potential antiviral strategy by modulating SIRT2 activity.
10.15252/embr.202357500