scholarly journals Widespread PERK-dependent repression of ER targets in response to ER stress

2018 ◽  
Author(s):  
Nir Gonen ◽  
Niv Sabath ◽  
Christopher B. Burge ◽  
Reut Shalgi
Keyword(s):  
Gene Expression ◽  
Stress Response ◽  
Er Stress ◽  
Stress Responses ◽  
Disulfide Bonds ◽  
Mammalian Cells ◽  
Early Gene ◽  
Short Exposure ◽  
Er Stress Response ◽  
Specific Subset

AbstractThe UPR (Unfolded Protein Response) is a well-orchestrated response to ER protein folding and processing overload, integrating both transcriptional and translational outputs. Its three arms in mammalian cells, the PERK translational response arm, together with the ATF6 and IRE1-XBP1-mediated transcriptional arms, have been thoroughly investigated.Using ribosome footprint profiling, we performed a deep characterization of gene expression programs involved in the early and late ER stress responses, within WT or PERK -/- Mouse Embryonic Fibroblasts (MEFs). We found that both repression and activation gene expression programs, affecting hundreds of genes, are significantly hampered in the absence of PERK. Specifically, PERK -/- cells do not show global translational inhibition, nor do they specifically activate early gene expression programs upon short exposure to ER stress. Furthermore, while PERK -/- cells do activate/repress late ER-stress response genes, the response is substantially weaker. Importantly, we highlight a widespread PERK-dependent repression gene expression program, consisting of ER targeted proteins, including transmembrane proteins, glycoproteins, and proteins with disulfide bonds. This phenomenon occurs in various different cell types, and has a major translational regulatory component. Moreover, we revealed a novel interplay between PERK and the XBP1-ATF6 arms of the UPR, whereby PERK attenuates the expression of a specific subset of XBP1-ATF6 targets, further illuminating the complexity of the integrated ER stress response.

scholarly journals Conserved Roles of C. elegans and Human MANFs in Sulfatide Binding and Cytoprotection

2018 ◽  
Author(s):  
Meirong Bai ◽  
Roman Vozdek ◽  
Aleš Hnízda ◽  
Chenxiao Jiang ◽  
Bingying Wang ◽  
...  
Keyword(s):  
Stress Response ◽  
Er Stress ◽  
Stress Responses ◽  
Mammalian Cells ◽  
Dopamine Neurons ◽  
Lipid Mediator ◽  
Outer Cell ◽  
Dependent Manner ◽  
C Elegans ◽  
Er Stress Response

AbstractMesencephalic Astrocyte-Derived Neurotrophic Factor (MANF) is an endoplasmic reticulum (ER) protein that can be secreted and protect dopamine neurons and cardiomyocytes from ER stress and apoptosis. The mechanism of action of extracellular MANF has long been elusive. From a genetic screen for mutants with abnormal ER stress response, we identified the gene Y54G2A.23 as the evolutionarily conserved C. elegans MANF orthologue. We find that MANF binds to the lipid sulfatide, also known as 3-O-sulfogalactosylceramide present in serum and outer-cell membrane leaflets, directly in isolated forms and in reconstituted lipid micelles. Sulfatide binding promotes cellular MANF uptake and cytoprotection from hypoxia-induced cell death. Heightened ER stress responses of MANF-null C. elegans mutants and mammalian cells are alleviated by human MANF in a sulfatide-dependent manner. Our results demonstrate conserved roles of MANF in sulfatide binding and ER stress response, supporting sulfatide as a long-sought lipid mediator of MANF’s cytoprotection.

Epstein-Barr Virus and Kaposi's Sarcoma Herpesvirus Lytic Cycle Induction with Bortezomib Is a Response to ER Stress

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1736-1736 ◽  
Author(s):  
Courtney O'Farrell ◽  
Meir Shamay ◽  
Nene Kalu ◽  
Andrew DuFresne ◽  
Sunetra Biswas ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stress Response ◽  
Er Stress ◽  
Cell Lines ◽  
Family Members ◽  
Lytic Cycle ◽  
Early Gene ◽  
Immediate Early ◽  
Antitumor Effects ◽  
Er Stress Response

Abstract Abstract 1736 EBV and KSHV are associated with a variety of lymphoid malignancies. Bortezomib, a proteasome inhibitor, is among the most potent activators of EBV and KSHV lytic infection and is active at nanomolar concentrations. Studying EBV Burkitt's cell lines, KSHV primary effusion lymphoma cell lines and EBV myeloma cell lines, we found that lytic gene expression is a class effect shared by other proteasome inhibitors, such as MG-132 and epoxomicin. Proteasome inhibition results in IKB stabilization and inhibition of NFKB activity and this effect has been implicated in many of the effects of bortezomib. We studied the promoters of EBV and KSHV immediate early viral protein reporters (EBV Zta and KSHV Rta) and found that IKB super-repressor did not activate promoter reporters suggesting that other pathways must be important in activation. Therefore, we sought to better understand the drug's impact on viral gene expression in virus-associated tumor cells. ER stress has been implicated in bortezomib's antitumor effects. Thapsigargin and tunicamycin are classic activators of ER stress that do not act through proteasomal inhibition. These agents were found to be potent activators of the EBV and KSHV lytic cycle. Previous studies have identified C/EBP family members (C/EBP alpha and beta) as activators of EBV and KSHV immediate early gene expression. In other studies, C/EBP family members (C/EBP beta, CHOP10) have been implicated in regulating the ER stress response. We found that bortezomib, thapsigargin and tunicamycin increased levels of the activating C/EBP beta LAP isoform as assessed by immunoblot and by real-time RT-PCR. Treatment also led to increase in ATF4, XBP1(s), CHOP10, and ATF6 cleavage, all consistent with induction of the ER stress response. Additionally, we showed that treatment with bortezomib increased C/EBP beta binding to previously characterized binding sites in the Zta promoter and expression of C/EBP beta LAP isoform was sufficient to activate EBV immediate early lytic promoters. Finally, we demonstrated that in tumor cell lines with C/EBP beta silenced by doxycycline regulated siRNA, induction of EBV lytic induction by bortezomib and thapsigargin was blocked. These results demonstrate that both human lymphoma associated herpesviruses (EBV and KSHV) are activated into lytic cycle by bortezomib and that these effects are mediated through ER stress pathways and specifically involve C/EBP beta. Disclosures: No relevant conflicts of interest to declare.

Abstract 211: ATF6 and the Adaptive ER Stress Response Enhances Proliferation and Viability in Mouse Cardiac Stem Cells

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Winston T Stauffer ◽  
Shirin Doroudgar ◽  
Haley N Stephens ◽  
Brandi Bailey ◽  
Christopher C Glembotski
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Stress Response ◽  
Er Stress ◽  
Ischemic Heart ◽  
Cardiac Stem Cells ◽  
Response Gene ◽  
Er Stress Response ◽  
Chemical Inhibition ◽  
Stress Response Gene

Rationale: Cardiac stem cells (CSCs) are beneficial when administered to infarcted mouse or rat hearts. Though the mechanism of these benefits is unknown, CSC vitality likely plays a major role. Thus, investigating the factors governing CSC survival in the ischemic heart may lead to more effective therapeutic strategies. Our previous studies showed that misfolded proteins accumulate in the sarco/endoplasmic reticulum (SR/ER) of the ischemic heart. The transcription factor, ATF6, is a key component of the adaptive ER stress response because it induces genes that reduce the accumulation of misfolded proteins, improving myocyte survival during ischemic stress. While our lab has shown that, in cardiac myocytes, ATF6 is cardioprotective in the ischemic heart, neither the ER stress response nor ATF6 have been examined in CSCs. We hypothesize that ATF6 and the adaptive ER stress response are critical for optimal survival of CSCs. Objective/Methods: To gauge the relevance of the ER stress response in CSCs, we used MTT assays to compare the viabilities of mouse CSCs to neonatal rat ventricular myocytes (NRVM) subjected to treatments that mimic ischemic ER stress in the heart. We also assessed the effect of inhibiting ATF6 on both the ER stress response and CSC viability by using chemical inhibition of ATF6 activation or siRNA-mediated ATF6 knock down. Results: We found that, compared to NRVM, CSCs exhibited lower levels of adaptive ER stress response gene expression and decreased viability in response to ER stress. Thus, relative to NRVM, the adaptive ER stress response is not fully developed in CSCs. We also found that either chemical inhibition of ATF6 activation or ATF6 knock down decreased adaptive ER stress response gene expression. Strikingly, ATF6 inhibition or knockdown decreased CSC viability and cell number by as much as 70%. Conclusions: Thus, compared to cardiac myocytes, CSCs exhibit a reduced adaptive ER stress response and are more sensitive to ER stress, suggesting that enhancement of the ATF6-mediated adaptive ER stress response in CSCs may be a viable therapeutic approach for enhancing stem cell-mediated myocardial repair.

scholarly journals Endoplasmic reticulum stress response in the roadway for the effects of non-steroidal anti-inflammatory drugs

2015 ◽  
Vol 2 (1) ◽  
Author(s):  
Fernanda L.B. Mügge ◽  
Aristóbolo M. Silva
Keyword(s):  
Endoplasmic Reticulum ◽  
Stress Response ◽  
Er Stress ◽  
Stress Responses ◽  
Endoplasmic Reticulum Stress Response ◽  
The Road ◽  
Er Stress Response ◽  
Mediated Effects ◽  
Inflammatory Drugs ◽  
Anti Inflammatory

AbstractOver the past decade, a handful of evidence has been provided that nonsteroidal anti-inflammatory drugs (NSAIDs) display effects on the homeostasis of the endoplasmic reticulum (ER). Their uptake into cells will eventually lead to activation or inhibition of key molecules that mediate ER stress responses, raising not only a growing interest for a pharmacological target in ER stress responses but also important questions how the ER-stress mediated effects induced by NSAIDs could be therapeutically advantageous or not. We review here the toxicity effects and therapeutic applications of NSAIDs involving the three majors ER stress arms namely PERK, IRE1, and ATF6. First, we provide brief introduction on the well-established and characterized downstream events mediated by these ER stress players, followed by presentation of the NSAIDs compounds and mode of action, and finally their effects on ER stress response. NSAIDs present promising drug agents targeting the components of ER stress in different aspects of cancer and other diseases, but a better comprehension of the mechanisms underlying their benefits and harms will certainly pave the road for several diseases’ therapy.

XBP1U inhibits the XBP1S-mediated upregulation of the iNOS gene expression in mammalian ER stress response

2010 ◽  
Vol 22 (12) ◽  
pp. 1818-1828 ◽  
Author(s):  
FengJin Guo ◽  
Edward A. Lin ◽  
Ping Liu ◽  
Jianwei Lin ◽  
Chuanju Liu
Keyword(s):  
Gene Expression ◽  
Stress Response ◽  
Er Stress ◽  
Er Stress Response ◽  
Inos Gene ◽  
Inos Gene Expression

Bortezomib Induces an Antioxidant and ER-Stress Response Gene Expression Signature in Mantle Cell Lymphoma: Implications for Response Prediction and Optimized Chemotherapy Regimens.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 830-830
Author(s):  
Edgar G. Rizzatti ◽  
Helena Mora-Jensen ◽  
Raymond Lai ◽  
Masanori Daibata ◽  
Therese White ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stress Response ◽  
Er Stress ◽  
Mantle Cell Lymphoma ◽  
Cell Lines ◽  
Cell Lymphoma ◽  
Er Stress Response ◽  
Mantle Cell ◽  
Sensitive Group ◽  
Resistant Cells

Abstract Mantle cell lymphoma (MCL) is an aggressive and incurable B-cell lymphoma for which new treatment options are needed. Recent phase II clinical trials reported response to the proteasome inhibitor bortezomib (BZM) in up to 50% of pre-treated patients. Despite the successful use of BZM in the clinic, the precise molecular mechanisms underlying sensitivity or resistance to BZM in MCL remain largely unknown. To address this issue, we used U133A 2.0 microarrays to analyze gene expression in MCL cells from peripheral blood of 5 patients with previously untreated leukemic MCL. Samples were collected immediately before (0h) and at 3, 6, 24, and 72 hours after administration of BZM (1.5 mg/m2). After the blood collection at 72 hours, a second dose of BZM was given, and cells were collected 24 hours later. Two patients had major reductions in peripheral ALC already at 24h from dose 2 and normalized their blood counts by day 21 (sensitive), 1 patient had no change over a full course of 4 injections (resistant), and 2 patients had some decrease in ALC (intermediate). Genes differentially expressed with treatment were ranked according to the degree of correlation with time (Pearson). We used gene set enrichment analysis (GSEA) to detect distinct functional gene expression signatures; the most consistently up-regulated of which was a signature composed by proteasome and chaperone genes. To confirm and expand these findings, we exposed 10 MCL cell lines (7 sensitive, IC50<10nM; 3 resistant IC50>10nM) to 10nM of BZM and analyzed gene expression at 1, 3, 6 and 24 hours. The proteasome signature was again dominant, and the majority of the up-regulated genes in both clinical and cell line samples shared binding motifs for the NRF, MAF, ATF and HSF families of transcription factors (TF). Thus genes up-regulated by BZM in vivo and in cell lines predominantly belonged to a functional response to oxidative and/or endoplasmic reticulum (ER) stress. Under physiologic conditions, this is thought to help restore homeostasis and protect from apoptosis. This response could therefore contribute to drug resistance or be a marker of an overwhelming insult before the cells undergo apoptosis. To address this issue, we investigated differences in response to BZM between sensitive and resistant cell lines. The proteasome signature was more strongly up-regulated in sensitive cells than in resistant cells, and the ER-stress response as measured by genes controlled by the NRF and MAF family of TFs was also more highly expressed in the sensitive group. Consistently, expression of HMOX1, which encodes a key enzyme in the antioxidant response, was increased by 32× at 24h in the sensitive group, but only by 4× in the resistant group; the expression of DDIT3, a transcription factor implicated in a pro-apoptotic response to ER-stress was 5.5-fold up-regulated in the sensitive cells but only 1.4-fold in the resistant cells. We conclude that in sensitive cells BZM induces an overwhelming ER-stress response with high expression of proteasome components and chaperone proteins that could serve as a predictor of response to BZM.

Protective role for nitric oxide during the endoplasmic reticulum stress response in pancreatic β-cells

2007 ◽  
Vol 292 (6) ◽  
pp. E1543-E1554 ◽  
Author(s):  
Kajorn Kitiphongspattana ◽  
Tarannum A. Khan ◽  
Katrin Ishii-Schrade ◽  
Michael W. Roe ◽  
Louis H. Philipson ◽  
...  
Keyword(s):  
Gene Expression ◽  
Endoplasmic Reticulum ◽  
Stress Response ◽  
Er Stress ◽  
Antioxidant Defense ◽  
Protective Role ◽  
No Production ◽  
Β Cell ◽  
Er Stress Response ◽  
Mouse Islets

Higher requirements for disulfide bond formation in professional secretory cells may affect intracellular redox homeostasis, particularly during an endoplasmic reticulum (ER) stress response. To assess this hypothesis, we investigated the effects of the ER stress response on the major redox couple (GSH/GSSG), endogenous ROS production, expression of genes involved in ER oxidative protein folding, general antioxidant defense, and thiol metabolism by use of the well-validated MIN6 β-cell as a model and mouse islets. The data revealed that glucose concentration-dependent decreases in the GSH/GSSG ratio were further decreased significantly by ER-derived oxidative stress induced by inhibiting ER-associated degradation with the specific proteasome inhibitor lactacystin (10 μM) in mouse islets. Notably, minimal cell death was observed during 12-h treatments. This was likely attributed to the upregulation of genes encoding the rate limiting enzyme for glutathione synthesis (γ-glutamylcysteine ligase), as well as genes involved in antioxidant defense (glutathione peroxidase, peroxiredoxin-1) and ER protein folding ( Grp78/BiP, PDI, Ero1). Gene expression and reporter assays with a NO synthase inhibitor ( Nω-nitro-l-arginine methyl ester, 1–10 mM) indicated that endogenous NO production was essential for the upregulation of several ER stress-responsive genes. Specifically, gel shift analyses demonstrate NO-independent binding of the transcription factor NF-E2-related factor to the antioxidant response element Gclc-ARE4 in MIN6 cells. However, endogenous NO production was necessary for activation of Gclc-ARE4-driven reporter gene expression. Together, these data reveal a distinct protective role for NO during the ER stress response, which helps to dissipate ROS and promote β-cell survival.

scholarly journals Small heterodimer partner (SHP) aggravates ER stress in Parkinson’s disease-linked LRRK2 mutant astrocyte by regulating XBP1 SUMOylation

2021 ◽  
Vol 28 (1) ◽  
Author(s):  
Jee Hoon Lee ◽  
Ji-hye Han ◽  
Eun-hye Joe ◽  
Ilo Jou
Keyword(s):  
Gene Expression ◽  
Cell Death ◽  
Stress Response ◽  
Er Stress ◽  
Gene Expression Profiling ◽  
Expression Profiling ◽  
Er Stress Response ◽  
Small Heterodimer Partner ◽  
Lrrk2 G2019s ◽  
Mutant Lrrk2

Abstract Background Endoplasmic reticulum (ER) stress is a common feature of Parkinson’s disease (PD), and several PD-related genes are responsible for ER dysfunction. Recent studies suggested LRRK2-G2019S, a pathogenic mutation in the PD-associated gene LRRK2, cause ER dysfunction, and could thereby contribute to the development of PD. It remains unclear, however, how mutant LRRK2 influence ER stress to control cellular outcome. In this study, we identified the mechanism by which LRRK2-G2019S accelerates ER stress and cell death in astrocytes. Methods To investigate changes in ER stress response genes, we treated LRRK2-wild type and LRRK2-G2019S astrocytes with tunicamycin, an ER stress-inducing agent, and performed gene expression profiling with microarrays. The XBP1 SUMOylation and PIAS1 ubiquitination were performed using immunoprecipitation assay. The effect of astrocyte to neuronal survival were assessed by astrocytes-neuron coculture and slice culture systems. To provide in vivo proof-of-concept of our approach, we measured ER stress response in mouse brain. Results Microarray gene expression profiling revealed that LRRK2-G2019S decreased signaling through XBP1, a key transcription factor of the ER stress response, while increasing the apoptotic ER stress response typified by PERK signaling. In LRRK2-G2019S astrocytes, the transcriptional activity of XBP1 was decreased by PIAS1-mediated SUMOylation. Intriguingly, LRRK2-GS stabilized PIAS1 by increasing the level of small heterodimer partner (SHP), a negative regulator of PIAS1 degradation, thereby promoting XBP1 SUMOylation. When SHP was depleted, XBP1 SUMOylation and cell death were reduced. In addition, we identified agents that can disrupt SHP-mediated XBP1 SUMOylation and may therefore have therapeutic activity in PD caused by the LRRK2-G2019S mutation. Conclusion Our findings reveal a novel regulatory mechanism involving XBP1 in LRRK2-G2019S mutant astrocytes, and highlight the importance of the SHP/PIAS1/XBP1 axis in PD models. These findings provide important insight into the basis of the correlation between mutant LRRK2 and pathophysiological ER stress in PD, and suggest a plausible model that explains this connection.

scholarly journals Mechanisms of Alcohol-Induced Endoplasmic Reticulum Stress and Organ Injuries

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Cheng Ji
Keyword(s):  
Endoplasmic Reticulum ◽  
Stress Response ◽  
Er Stress ◽  
Stress Responses ◽  
Iron Homeostasis ◽  
Blood Stream ◽  
The Body ◽  
Excessive Alcohol Consumption ◽  
Er Stress Response ◽  
Therapeutic Benefits

Alcohol is readily distributed throughout the body in the blood stream and crosses biological membranes, which affect virtually all biological processes inside the cell. Excessive alcohol consumption induces numerous pathological stress responses, part of which is endoplasmic reticulum (ER) stress response. ER stress, a condition under which unfolded/misfolded protein accumulates in the ER, contributes to alcoholic disorders of major organs such as liver, pancreas, heart, and brain. Potential mechanisms that trigger the alcoholic ER stress response are directly or indirectly related to alcohol metabolism, which includes toxic acetaldehyde and homocysteine, oxidative stress, perturbations of calcium or iron homeostasis, alterations of S-adenosylmethionine to S-adenosylhomocysteine ratio, and abnormal epigenetic modifications. Interruption of the ER stress triggers is anticipated to have therapeutic benefits for alcoholic disorders.

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