Association of GRP78 promoter polymorphisms and serum GRP78 level with risk of asthenozoospermia.
Qin Haimei,Wang Rong,Pang Xiaoxia,Wei Yuxiao,Yang Fenglian,Wang Junli
Journal of assisted reproduction and genetics
PURPOSE:The aim of this study was undertaken to investigate the association of 78-kDa glucose-regulated protein (GRP78) gene promoter polymorphisms with risk of asthenozoospermia (AZS) men. In addition, we performed association analysis between GRP78 promoter mutations and serum GRP78 level in asthenozoospermia. METHODS:The study population comprised 400 subjects with AZS patients and 400 healthy controls. We assessed GRP78 rs3216733, rs17840761, and rs17840762 polymorphisms by using Snapshot SNP genotyping assays; serum GRP78 level was measured by enzyme-linked immunosorbent assay (ELISA). Semen quality was assessed by computer-assisted semen analysis. RESULTS:We found that rs3216733 was associated with increased risk of AZS (Gd vs. dd: adjusted OR = 1.42, 95% CI, 1.06-1.93, P = 0.020; Gd/GG vs. dd: adjusted OR = 1.43, 95% CI, 1.08-1.91, P = 0.013; G vs. d adjusted OR = 1.26, 95% CI, 1.03-1.56, P = 0.027). The haplotype analyses showed the frequency of G-C-C haplotype was significantly higher in AZS (P = 0.026). The percentage of progressive motility sperm was lower in the asthenozoospermic men with Gd and Gd/GG genotypes than dd genotype (P = 0.003). Moreover, the serum GRP78 levels were significantly lower in rs3216733 Gd/GG genotypes compared with the dd genotype (P < 0.001). CONCLUSION:Our findings suggest that rs3216733 Gd/GG genotypes contribute to poor sperm motility, probably by decreasing the level of GRP78.
10.1007/s10815-018-1316-0
The reproductive toxicology of male SD rats after PM exposure mediated by the stimulation of endoplasmic reticulum stress.
Liu Xiaona,Jin Xiaoting,Su Ruijun,Li Zhuoyu
Chemosphere
Evidence has shown that exposure to fine particulate matter (PM) contributed to poor semen quality in males. However, the reproductive toxicity and relevant molecular mechanisms of Particular Matter 2.5 (PM) from different seasons are not well understood. In the present work, we intend to investigate the toxic effects of PM during summer and winter on reproductive cells and tissues and focus on endoplasmic reticulum stress (ERS) to illustrate the possible molecular mechanisms. Sprague Dawley (SD) rats were exposed to PM from the summer season (0.2, 0.6, and 1.5 mg/kg b. w.) and winter (0.3, 1.5, and 2.7 mg/kg b. w.) through intratracheal instillation. The exposure was performed once every 3 days and continued for 2 months. Sperm and reproductive organs (testis and epididymis) were collected from the animals to conduct toxicity evaluation and mechanism analysis. The data showed that sperm relative motility rates were remarkably decreased, while sperm malformation rates were significantly increased with exposure to the summer and winter PM. In particular, the reproductive toxicity of winter PM in the highest dose group was significantly greater than that in the other PM exposure groups. The pathological results also showed that the rats in the winter PM group of 2.7 mg/kg b. w. had severe testicular tissue injury, as determined by haematoxylin and eosin (HE) staining. The apoptotic results obtained by terminal dUTP nick-end labelling (TUNEL) further suggested that summer and winter PM exposure promoted the testicular germ cell apoptosis. The reproductive toxicity of winter PM in the testis was stronger than that of summer PM. In addition, the expressions of GRP78 and XBP-1, biomarkers of ERS, was enhanced under the conditions of PM exposure, and ERS-mediated apoptosis through the upregulation of CHOP and Caspase-12 in the epididymis and testis was activated. In conclusion, PM exposure induced reproductive toxicity in male SD rats by the stimulation of ERS.
10.1016/j.chemosphere.2017.09.082
ER and Nutrient Stress Promote Assembly of Respiratory Chain Supercomplexes through the PERK-eIF2α Axis.
Balsa Eduardo,Soustek Meghan S,Thomas Ajith,Cogliati Sara,García-Poyatos Carolina,Martín-García Elena,Jedrychowski Mark,Gygi Steve P,Enriquez José Antonio,Puigserver Pere
Molecular cell
Endoplasmic reticulum (ER) stress and unfolded protein response are energetically challenging under nutrient stress conditions. However, the regulatory mechanisms that control the energetic demand under nutrient and ER stress are largely unknown. Here we show that ER stress and glucose deprivation stimulate mitochondrial bioenergetics and formation of respiratory supercomplexes (SCs) through protein kinase R-like ER kinase (PERK). Genetic ablation or pharmacological inhibition of PERK suppresses nutrient and ER stress-mediated increases in SC levels and reduces oxidative phosphorylation-dependent ATP production. Conversely, PERK activation augments respiratory SCs. The PERK-eIF2α-ATF4 axis increases supercomplex assembly factor 1 (SCAF1 or COX7A2L), promoting SCs and enhanced mitochondrial respiration. PERK activation is sufficient to rescue bioenergetic defects caused by complex I missense mutations derived from mitochondrial disease patients. These studies have identified an energetic communication between ER and mitochondria, with implications in cell survival and diseases associated with mitochondrial failures.
10.1016/j.molcel.2019.03.031
Oleic acid ameliorates palmitic acid-induced ER stress and inflammation markers in naive and cerulein-treated exocrine pancreas cells.
Ben-Dror Karin,Birk Ruth
Bioscience reports
Dietary fat overload (typical to obesity) increases the risk of pancreatic pathologies through mechanisms yet to be defined. We previously showed that saturated dietary fat induces pancreatic acinar lipotoxicity and cellular stress. The endoplasmic reticulum (ER) of exocrine pancreas cells is highly developed and thus predisposed to stress. We studied the combination of saturated and unsaturated FAs in metabolic and pancreatitis like cerulein (CER)-induced stress states on cellular ER stress.Exocrine pancreas AR42J and rat primary exocrine acinar cells underwent acute (24 h) challenge with different FAs (saturated, monounsaturated) at different concentrations (250 and 500 µM) and in combination with acute CER-induced stress, and were analyzed for fat accumulation, ER stress unfolded protein response (UPR) and immune and enzyme markers. Acute exposure of AR42J and pancreatic acinar cells to different FAs and their combinations increased triglyceride accumulation. Palmitic acid significantly dose-dependently enhanced the UPR, immune factors and pancreatic lipase (PL) levels, as demonstrated by XBP1 splicing and elevation in UPR transcripts and protein levels ( and ). Exposure to high palmitic levels in a CER-induced stress state synergistically increased ER stress and inflammation marker levels. Exposure to oleic acid did not induce ER stress and PL levels and significantly decreased immune factors in an acute CER-induced stress state. Combination of oleic and palmitic acids significantly reduced the palmitic-induced ER stress, but did not affect the immune factor response. We show that combination of monounsaturated and saturated FAs protects from exocrine pancreatic cellular ER stress in both metabolic and CER-induced stress.
10.1042/BSR20190054
NK cells induce hepatic ER stress to promote insulin resistance in obesity through osteopontin production.
Wu Junhua,Wu Danyang,Zhang Longyao,Lin Chuxuan,Liao Jiahao,Xie Ruyin,Li Zhulin,Wu Siyang,Liu Aimin,Hu Weining,Xi Yang,Bu Shizhong,Wang Fuyan
Journal of leukocyte biology
High-fat diet (HFD) induced hepatic endoplasmic reticulum (ER) stress drives insulin resistance (IR) and steatosis. NK cells in adipose tissue play an important role in the pathogenesis of IR in obesity. Whether NK cells in the liver can induce hepatic ER stress and thus promote IR in obesity is still unknown. We demonstrate that HFD-fed mice display elevated production of proinflammatory cytokine osteopontin (OPN) in hepatic NK cells, especially in CD49a DX5 tissue-resident NK (trNK) cells. Obesity-induced ER stress, IR, and steatosis in the liver are ameliorated by ablating NK cells with neutralizing antibody in HFD-fed mice. OPN treatment enhances the expression of ER stress markers, including p-PERK, p-eIF2, ATF4, and CHOP in both murine liver tissues and HL-7702, a human liver cell line. Pretreatment of HL-7702 cells with OPN promotes hyperactivation of JNK and subsequent decrease of tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1), resulting in impaired insulin signaling, which can be reversed by inhibiting ER stress. Collectively, we demonstrate that hepatic NK cells induce obesity-induced hepatic ER stress, and IR through OPN production.
10.1002/JLB.3MA1119-173R
Ginsenoside Mc1 improves liver steatosis and insulin resistance by attenuating ER stress.
Roh Eun,Hwang Hwan-Jin,Kim Joo Won,Hong So-Hyeon,Kim Jung A,Lee You-Bin,Choi Kyung Mook,Baik Sei Hyun,Yoo Hye Jin
Journal of ethnopharmacology
ETHNOPHARMACOLOGICAL RELEVANCE:Ginsenoside, a major pharmacologically active ingredient in ginseng, has been known to exhibit beneficial properties such as antioxidant and anti-inflammatory effects. Ginsenoside compound Mc1 is one of the newly identified de-glycosylated ginsenosides. Endoplasmic reticulum (ER) stress has implicated in the development of non-alcoholic fatty liver disease (NAFLD) through apoptosis and lipid accumulation. AIM OF THE STUDY:We aimed to examine the protective effects of Mc1 treatment on ER stress-induced cell death and impaired insulin signaling in HepG2 human hepatoblastoma cells and ER stress-induced liver steatosis and insulin resistance in a diet-induced obesity (DIO) mouse model. MATERIALS AND METHODS:HepG2 cells were treated with palmitate and Mc1 to evaluate the effects of Mc1 on ER stress-induced damage. C57BL/6 mice were fed with a high-fat diet (HFD) for 4 weeks and received an intraperitoneal injection of either vehicle or Mc1 (10 mg/kg/day). The control mice were fed with a chow diet and injected with vehicle for the same period. ER stress, cell death, and degree of steatosis were evaluated in the liver tissues of mice. The effect of Mc1 treatment on glucose metabolism was also determined. RESULTS:Mc1 co-treatment reduced the palmitate-induced ER stress and death of HepG2 cells. The palmitate-induced insulin resistance improved after Mc1 co-treatment. Consistent with the in vitro data, chronic Mc1 supplementation reduced ER stress and apoptotic damage in the liver of obese mice. Mc1 treatment ameliorated glucose intolerance and insulin resistance through the suppression of c-Jun N-terminal kinase (JNK) phosphorylation. In addition, Mc1 treatment reduced obesity-induced lipogenesis and prevented fat accumulation in the liver of DIO mice. CONCLUSIONS:Mc1 exerted protective effects against ER stress-induced apoptotic damage, insulin resistance and lipogenesis in palmitate-treated hepatocytes and in the liver of DIO mice. Therefore, Mc1 supplementation could be a potential therapeutic strategy to prevent NAFLD in patients with obesity and insulin resistance.
10.1016/j.jep.2020.112927
Natural Products Targeting ER Stress, and the Functional Link to Mitochondria.
Martucciello Stefania,Masullo Milena,Cerulli Antonietta,Piacente Sonia
International journal of molecular sciences
The endoplasmic reticulum (ER) is a dynamic organelle essential for intracellular homeostasis maintenance, controlling synthesis, the folding of secreted and membrane-bound proteins, and transport of Ca. During cellular stress, ER dysfunction leads to the activation of unfolded protein response (UPR) due to accumulated misfolded proteins in the ER. This condition is referred as ER stress. Mitochondria and ER form a site of close contact (the mitochondria-associated membrane, MAM) which is a major platform exerting important physiological roles in the regulation of intracellular Ca homeostasis, lipid metabolism, mitochondrial fission, autophagosome formation, and apoptosis progression. Natural products have been receiving increasing attention for their ability to interfere with ER stress. Research works have focused on the capacity of these bioactive compounds to induce apoptosis by activating ER stress through the ER stress-mediated mitochondrial apoptotic pathway. In this review we discuss the role of natural products in the signaling communication between ER and mitochondria, focusing on the effects induced by ER stress including Ca permeability transition and UPR signaling (protein kinase R-like ER kinase/mitofusin 2).
10.3390/ijms21061905
Mitochondria and T2D: Role of Autophagy, ER Stress, and Inflammasome.
Rocha Milagros,Apostolova Nadezda,Diaz-Rua Ruben,Muntane Jordi,Victor Victor M
Trends in endocrinology and metabolism: TEM
Type 2 diabetes (T2D) is one of the main current threats to human health. Both T2D and its numerous clinical complications are related to mitochondrial dysfunction and oxidative stress. Over the past decade, great progress has been made in extending our knowledge about the signaling events regulated by mitochondria. However, the links among mitochondrial impairment, oxidative stress, autophagy, endoplasmic reticulum (ER) stress, and activation of the inflammasome still need to be clarified. In light of this deficit, we aim to provide a review of the existing literature concerning the complicated crosstalk between mitochondrial impairment, autophagy, ER stress, and the inflammasome in the molecular pathogenesis of T2D.
10.1016/j.tem.2020.03.004
[ER stress and NAFLD].
Biologie aujourd'hui
Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent pathology associated with obesity. It encompasses a spectrum of hepatic disorders ranging from steatosis to non-alcoholic steatohepatitis (NASH), which may lead to cirrhosis and hepatocellular carcinoma (HCC). Endoplasmic reticulum (ER) stress has been widely involved to drive in NAFLD progression through the activation of the unfolded protein response (UPR). While transient UPR activation can boost hepatic ER functions, its continuous activation upon a chronic ER stress contributes to lipid accumulation, inflammation and hepatocyte death, which are determinant factors for the progression to more severe stages. The aim of this review is to describe the mechanisms through which the UPR can take part in the transition from a healthy to a diseased liver and to report on possible ways of pharmacological manipulation against these pathological mechanisms.
10.1051/jbio/2020007
ER Stress Inhibits Liver Fatty Acid Oxidation while Unmitigated Stress Leads to Anorexia-Induced Lipolysis and Both Liver and Kidney Steatosis.
DeZwaan-McCabe Diane,Sheldon Ryan D,Gorecki Michelle C,Guo Deng-Fu,Gansemer Erica R,Kaufman Randal J,Rahmouni Kamal,Gillum Matthew P,Taylor Eric B,Teesch Lynn M,Rutkowski D Thomas
Cell reports
The unfolded protein response (UPR), induced by endoplasmic reticulum (ER) stress, regulates the expression of factors that restore protein folding homeostasis. However, in the liver and kidney, ER stress also leads to lipid accumulation, accompanied at least in the liver by transcriptional suppression of metabolic genes. The mechanisms of this accumulation, including which pathways contribute to the phenotype in each organ, are unclear. We combined gene expression profiling, biochemical assays, and untargeted lipidomics to understand the basis of stress-dependent lipid accumulation, taking advantage of enhanced hepatic and renal steatosis in mice lacking the ER stress sensor ATF6α. We found that impaired fatty acid oxidation contributed to the early development of steatosis in the liver but not the kidney, while anorexia-induced lipolysis promoted late triglyceride and free fatty acid accumulation in both organs. These findings provide evidence for both direct and indirect regulation of peripheral metabolism by ER stress.
10.1016/j.celrep.2017.05.020
SELENON (SEPN1) protects skeletal muscle from saturated fatty acid-induced ER stress and insulin resistance.
Varone Ersilia,Pozzer Diego,Di Modica Simona,Chernorudskiy Alexander,Nogara Leonardo,Baraldo Martina,Cinquanta Mario,Fumagalli Stefano,Villar-Quiles Rocio Nur,De Simoni Maria-Grazia,Blaauw Bert,Ferreiro Ana,Zito Ester
Redox biology
Selenoprotein N (SELENON) is an endoplasmic reticulum (ER) protein whose loss of function leads to a congenital myopathy associated with insulin resistance (SEPN1-related myopathy). The exact cause of the insulin resistance in patients with SELENON loss of function is not known. Skeletal muscle is the main contributor to insulin-mediated glucose uptake, and a defect in this muscle-related mechanism triggers insulin resistance and glucose intolerance. We have studied the chain of events that connect the loss of SELENON with defects in insulin-mediated glucose uptake in muscle cells and the effects of this on muscle performance. Here, we show that saturated fatty acids are more lipotoxic in SELENON-devoid cells, and blunt the insulin-mediated glucose uptake of SELENON-devoid myotubes by increasing ER stress and mounting a maladaptive ER stress response. Furthermore, the hind limb skeletal muscles of SELENON KO mice fed a high-fat diet mirrors the features of saturated fatty acid-treated myotubes, and show signs of myopathy with a compromised force production. These findings suggest that the absence of SELENON together with a high-fat dietary regimen increases susceptibility to insulin resistance by triggering a chronic ER stress in skeletal muscle and muscle weakness. Importantly, our findings suggest that environmental cues eliciting ER stress in skeletal muscle (such as a high-fat diet) affect the pathological phenotype of SEPN1-related myopathy and can therefore contribute to the assessment of prognosis beyond simple genotype-phenotype correlations.
10.1016/j.redox.2019.101176
Lipid environment induces ER stress, TXNIP expression and inflammation in immune cells of individuals with type 2 diabetes.
Szpigel Anaïs,Hainault Isabelle,Carlier Aurélie,Venteclef Nicolas,Batto Anne-Françoise,Hajduch Eric,Bernard Catherine,Ktorza Alain,Gautier Jean-François,Ferré Pascal,Bourron Olivier,Foufelle Fabienne
Diabetologia
AIMS/HYPOTHESIS:Obesity and type 2 diabetes are concomitant with low-grade inflammation affecting insulin sensitivity and insulin secretion. Recently, the thioredoxin interacting protein (TXNIP) has been implicated in the activation process of the NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome. In this study, we aim to determine whether the expression of TXNIP is altered in the circulating immune cells of individuals with type 2 vs type 1 diabetes and whether this can be related to specific causes and consequences of inflammation. METHODS:The expression of TXNIP, inflammatory markers, markers of the unfolded protein response (UPR) to endoplasmic reticulum (ER) stress and enzymes involved in sphingolipid metabolism was quantified by quantitative reverse transcription real-time PCR (qRT-PCR) in peripheral blood mononuclear cells (PBMCs) of 13 non-diabetic individuals, 23 individuals with type 1 diabetes and 81 with type 2 diabetes. A lipidomic analysis on the plasma of 13 non-diabetic individuals, 35 individuals with type 1 diabetes and 94 with type 2 diabetes was performed. The effects of ER stress or of specific lipids on TXNIP and inflammatory marker expression were analysed in human monocyte-derived macrophages (HMDMs) and THP-1 cells. RESULTS:The expression of TXNIP and inflammatory and UPR markers was increased in the PBMCs of individuals with type 2 diabetes when compared with non-diabetic individuals or individuals with type 1 diabetes. TXNIP expression was significantly correlated with plasma fasting glucose, plasma triacylglycerol concentrations and specific UPR markers. Induction of ER stress in THP-1 cells or cultured HMDMs led to increased expression of UPR markers, TXNIP, NLRP3 and IL-1β. Conversely, a chemical chaperone reduced the expression of UPR markers and TXNIP in PBMCs of individuals with type 2 diabetes. The lipidomic plasma analysis revealed an increased concentration of saturated dihydroceramide and sphingomyelin in individuals with type 2 diabetes when compared with non-diabetic individuals and individuals with type 1 diabetes. In addition, the expression of specific enzymes of sphingolipid metabolism, dihydroceramide desaturase 1 and sphingomyelin synthase 1, was increased in the PBMCs of individuals with type 2 diabetes. Palmitate or C2 ceramide induced ER stress in macrophages as well as increased expression of TXNIP, NLRP3 and IL-1β. CONCLUSIONS/INTERPRETATION:In individuals with type 2 diabetes, circulating immune cells display an inflammatory phenotype that can be linked to ER stress and TXNIP expression. Immune cell ER stress can in turn be linked to the specific exogenous and endogenous lipid environment found in type 2 diabetes.
10.1007/s00125-017-4462-5
Effect of ER stress on sphingolipid levels and apoptotic pathways in retinal pigment epithelial cells.
Afşar Ebru,Kırımlıoglu Esma,Çeker Tuğçe,Yılmaz Çağatay,Demir Necdet,Aslan Mutay
Redox biology
BACKGROUND:We aimed to determine sphingolipid levels and examine apoptotic pathways in human retinal pigment epithelial cells (ARPE-19) undergoing endoplasmic reticulum (ER) stress. METHODS:Cells were treated with tunicamycin (TM) to induce ER stress and tauroursodeoxycholic acid (TUDCA), an ER stress inhibitor, was administered to decrease cytotoxicity. Cell viability was measured by MTT assay. Levels of C16-C24 sphingomyelins (SM) and C16-C24 ceramides (CERs) were determined by LC-MS/MS. Glucose-regulated protein 78-kd (GRP78) and nuclear factor kappa-b subunit 1 (NFκB1) gene expressions were evaluated by quantitative PCR analysis, while GRP 78, NF-κB p65, cleaved caspase-3 and caspase-12 protein levels were assesed by immunofluorescence. Ceramide-1-phosphate (C1P) levels were determined by immunoassay, while caspase -3 and -12 activity in cell lysates were measured via a fluorometric method. RESULTS:Induction of ER stress in TM treated groups were confirmed by significantly increased mRNA and protein levels of GRP78. TM significantly decreased cell viability compared to controls. Treatment with TUDCA along with TM significantly increased cell viability compared to the TM group. A significant increase was observed in C22-C24 CERs, C1P, caspase-3, caspase-12, NFκB1 mRNA and NF-κB p65 protein levels in cells treated with TM compared to controls. Administration of TUDCA lead to a partial decrease in GRP78 expression, NFκB1 mRNA, NF-κB p65 protein, C22-C24 CERs and C1P levels along with a decrease in caspase-3 and -12 activity. CONCLUSIONS:The results of this study reveal the presence of increased long chain CERs, C1P and apoptotic markers in retinal cells undergoing ER stress.
10.1016/j.redox.2020.101430
Membrane dynamics and protein targets of lipid droplet microautophagy during ER stress-induced proteostasis in the budding yeast, .
Garcia Enrique J,Liao Pin-Chao,Tan Gary,Vevea Jason D,Sing Cierra N,Tsang Catherine A,McCaffery J Michael,Boldogh Istvan R,Pon Liza A
Autophagy
Our previous studies reveal a mechanism for lipid droplet (LD)-mediated proteostasis in the endoplasmic reticulum (ER) whereby unfolded proteins that accumulate in the ER in response to lipid imbalance-induced ER stress are removed by LDs and degraded by microlipophagy (µLP), autophagosome-independent LD uptake into the vacuole (the yeast lysosome). Here, we show that dithiothreitol- or tunicamycin-induced ER stress also induces µLP and identify an unexpected role for vacuolar membrane dynamics in this process. All stressors studied induce vacuolar fragmentation prior to µLP. Moreover, during µLP, fragmented vacuoles fuse to form cup-shaped structures that encapsulate and ultimately take up LDs. Our studies also indicate that proteins of the endosome sorting complexes required for transport (ESCRT) are upregulated, required for µLP, and recruited to LDs, vacuolar membranes, and sites of vacuolar membrane scission during µLP. We identify possible target proteins for LD-mediated ER proteostasis. Our live-cell imaging studies reveal that one potential target (Nup159) localizes to punctate structures that colocalizes with LDs 1) during movement from ER membranes to the cytosol, 2) during microautophagic uptake into vacuoles, and 3) within the vacuolar lumen. Finally, we find that mutations that inhibit LD biogenesis, homotypic vacuolar membrane fusion or ESCRT function inhibit stress-induced autophagy of Nup159 and other ER proteins. Thus, we have obtained the first direct evidence that LDs and µLP can mediate ER stress-induced ER proteostasis, and identified direct roles for ESCRT and vacuolar membrane fusion in that process.
10.1080/15548627.2020.1826691
Phosphorylation switches protein disulfide isomerase activity to maintain proteostasis and attenuate ER stress.
Yu Jiaojiao,Li Tao,Liu Yu,Wang Xi,Zhang Jianchao,Wang Xi'e,Shi Guizhi,Lou Jizhong,Wang Likun,Wang Chih-Chen,Wang Lei
The EMBO journal
Accumulated unfolded proteins in the endoplasmic reticulum (ER) trigger the unfolded protein response (UPR) to increase ER protein folding capacity. ER proteostasis and UPR signaling need to be regulated in a precise and timely manner. Here, we identify phosphorylation of protein disulfide isomerase (PDI), one of the most abundant and critical folding catalysts in the ER, as an early event during ER stress. The secretory pathway kinase Fam20C phosphorylates Ser357 of PDI and responds rapidly to various ER stressors. Phosphorylation of Ser357 induces an open conformation of PDI and turns it from a "foldase" into a "holdase", which is critical for preventing protein misfolding in the ER. Phosphorylated PDI also binds to the lumenal domain of IRE1α, a major UPR signal transducer, and attenuates excessive IRE1α activity. Importantly, PDI-S359A knock-in mice display enhanced IRE1α activation and liver damage under acute ER stress. We conclude that the Fam20C-PDI axis constitutes a post-translational response to maintain ER proteostasis and plays a vital role in protecting against ER stress-induced cell death.
10.15252/embj.2019103841