scholarly journals O-GlcNAc signaling attenuates ER stress-induced cardiomyocyte death

2009 ◽  
Vol 297 (5) ◽  
pp. H1711-H1719 ◽  
Author(s):  
Gladys A. Ngoh ◽  
Tariq Hamid ◽  
Sumanth D. Prabhu ◽  
Steven P. Jones
Keyword(s):  
Cell Death ◽  
Er Stress ◽  
Cardiac Myocyte ◽  
Brefeldin A ◽  
Unfolded Protein ◽  
Homologous Protein ◽  
Stress Markers ◽  
The Unfolded Protein Response ◽  
Glcnac Transferase ◽  
Protein Response

We previously demonstrated that the O-linked β- N-acetylglucosamine ( O-GlcNAc) posttranslational modification confers cardioprotection at least partially through mitochondrial-dependent mechanisms, but it remained unclear if O-GlcNAc signaling interfered with other mechanisms of cell death. Because ischemia/hypoxia causes endoplasmic reticulum (ER) stress, we ascertained whether O-GlcNAc signaling could attenuate ER stress-induced cell death per se. Before induction of ER stress (with tunicamycin or brefeldin A), we adenovirally overexpressed O-GlcNAc transferase (AdOGT) or pharmacologically inhibited O-GlcNAcase [via O-(2-acetamido-2-deoxy-d-glucopyranosylidene) amino- N-phenylcarbamate] to augment O-GlcNAc levels or adenovirally overexpressed O-GlcNAcase to reduce O-GlcNAc levels. AdOGT significantly ( P < 0.05) attenuated the activation of the maladaptive arm of the unfolded protein response [according to C/EBP homologous protein (CHOP) activation] and cardiomyocyte death (reflected by percent propidium iodide positivity). Moreover, pharmacological inhibition of O-GlcNAcase significantly ( P < 0.05) mitigated ER stress-induced CHOP activation and cardiac myocyte death. Interestingly, overexpression of GCA did not alter ER stress markers but exacerbated brefeldin A-induced cardiomyocyte death. We conclude that enhanced O-GlcNAc signaling represents a partially proadaptive response to reduce ER stress-induced cell death. These results provide new insights into a possible interaction between O-GlcNAc signaling and ER stress and may partially explain a mechanism of O-GlcNAc-mediated cardioprotection.

scholarly journals Human Cytomegalovirus Protein pUL38 Induces ATF4 Expression, Inhibits Persistent JNK Phosphorylation, and Suppresses Endoplasmic Reticulum Stress-Induced Cell Death

2009 ◽  
Vol 83 (8) ◽  
pp. 3463-3474 ◽  
Author(s):  
Baoqin Xuan ◽  
Zhikang Qian ◽  
Emi Torigoi ◽  
Dong Yu
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Er Stress ◽  
Human Cytomegalovirus ◽  
Initiation Factor ◽  
Α Subunit ◽  
Unfolded Protein ◽  
Initiation Factor 2 ◽  
The Unfolded Protein Response ◽  
Protein Response

ABSTRACT The endoplasmic reticulum (ER) is a key organelle involved in sensing and responding to stressful conditions, including those resulting from infection of viruses, such as human cytomegalovirus (HCMV). Three signaling pathways collectively termed the unfolded protein response (UPR) are activated to resolve ER stress, but they will also lead to cell death if the stress cannot be alleviated. HCMV is able to modulate the UPR to promote its infection. The specific viral factors involved in such HCMV-mediated modulation, however, were unknown. We previously showed that HCMV protein pUL38 was required to maintain the viability of infected cells, and it blocked cell death induced by thapsigargin. Here, we report that pUL38 is an HCMV-encoded regulator to modulate the UPR. In infection, pUL38 allowed HCMV to upregulate phosphorylation of PKR-like ER kinase (PERK) and the α subunit of eukaryotic initiation factor 2 (eIF-2α), as well as induce robust accumulation of activating transcriptional factor 4 (ATF4), key components of the PERK pathway. pUL38 also allowed the virus to suppress persistent phosphorylation of c-Jun N-terminal kinase (JNK), which was induced by the inositol-requiring enzyme 1 pathway. In isolation, pUL38 overexpression elevated eIF-2α phosphorylation, induced ATF4 accumulation, limited JNK phosphorylation, and suppressed cell death induced by both thapsigargin and tunicamycin, two drugs that induce ER stress by different mechanisms. Importantly, ATF4 overexpression and JNK inhibition significantly reduced cell death in pUL38-deficient virus infection. Thus, pUL38 targets ATF4 expression and JNK activation, and this activity appears to be critical for protecting cells from ER stress induced by HCMV infection.

scholarly journals Acetaldehyde suppresses HBV-MHC class I complex presentation on hepatocytes via induction of ER stress and Golgi fragmentation

2020 ◽  
Vol 319 (4) ◽  
pp. G432-G442
Author(s):  
Murali Ganesan ◽  
Saumi Mathews ◽  
Edward Makarov ◽  
Armen Petrosyan ◽  
Kusum K. Kharbanda ◽  
...  
Keyword(s):  
Er Stress ◽  
Initiation Factor ◽  
Unfolded Protein ◽  
Homologous Protein ◽  
Histocompatibility Complex ◽  
B Virus ◽  
Golgi Fragmentation ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Golgi Network

Our current findings show that acetaldehyde accelerates endoplasmic reticulum (ER) stress by activating the unfolded protein response arms inositol-requiring enzyme 1α-X-box binding protein 1 and activation transcription factor (ATF)6α, but not phospho PKR-like ER kinase-phospho eukaryotic initiation factor 2α-ATF4-C/EBP homologous protein in hepatitis B virus (HBV)-transfected HepG2.2.15 cells. It also potentiates Golgi fragmentation, as evident by punctate distribution of Golgi proteins, GM130, trans-Golgi network 46, and Giantin. While concomitantly increasing HBV DNA and HBV surface antigen titers, acetaldehyde-induced ER stress suppresses the presentation of HBV peptide-major histocompatibility complex I complexes on hepatocyte surfaces, thereby promoting the persistence of HBV infection in the liver.

scholarly journals Regulation of podocyte survival and endoplasmic reticulum stress by fatty acids

2010 ◽  
Vol 299 (4) ◽  
pp. F821-F829 ◽  
Author(s):  
Jonas Sieber ◽  
Maja Tamara Lindenmeyer ◽  
Kapil Kampe ◽  
Kirk Nicholas Campbell ◽  
Clemens David Cohen ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Oleic Acid ◽  
Palmitic Acid ◽  
Er Stress ◽  
Unfolded Protein ◽  
Homologous Protein ◽  
Protein Response ◽  
Apoptosis And Necrosis

Apoptosis of podocytes is considered critical in the pathogenesis of diabetic nephropathy (DN). Free fatty acids (FFAs) are critically involved in the pathogenesis of diabetes mellitus type 2, in particular the regulation of pancreatic β cell survival. The objectives of this study were to elucidate the role of palmitic acid, palmitoleic, and oleic acid in the regulation of podocyte cell death and endoplasmic reticulum (ER) stress. We show that palmitic acid increases podocyte cell death, both apoptosis and necrosis of podocytes, in a dose and time-dependent fashion. Palmitic acid induces podocyte ER stress, leading to an unfolded protein response as reflected by the induction of the ER chaperone immunoglobulin heavy chain binding protein (BiP) and proapoptotic C/EBP homologous protein (CHOP) transcription factor. Of note, the monounsaturated palmitoleic and oleic acid can attenuate the palmitic acid-induced upregulation of CHOP, thereby preventing cell death. Similarly, gene silencing of CHOP protects against palmitic acid-induced podocyte apoptosis. Our results offer a rationale for interventional studies aimed at testing whether dietary shifting of the FFA balance toward unsaturated FFAs can delay the progression of DN.

scholarly journals Intracellular XBP1-IL-24 axis dismantles cytotoxic unfolded protein response in the liver

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Jianye Wang ◽  
Bian Hu ◽  
Zhicong Zhao ◽  
Haiyan Zhang ◽  
He Zhang ◽  
...  
Keyword(s):  
Cell Death ◽  
Er Stress ◽  
Initiation Factor ◽  
Dependent Manner ◽  
Unfolded Protein ◽  
Homologous Protein ◽  
Stress Signal ◽  
And Function ◽  
Protein Response ◽  
Er Homeostasis

AbstractEndoplasmic reticulum (ER) stress-associated cell death is prevalent in various liver diseases. However, the determinant mechanism how hepatocytes survive unresolved stress was still unclear. Interleukin-24 (IL-24) was previously found to promote ER stress-mediated cell death, and yet its expression and function in the liver remained elusive. Here we identified an antiapoptotic role of IL-24, which transiently accumulated within ER-stressed hepatocytes in a X-box binding protein 1 (XBP1)-dependent manner. Disruption of IL-24 increased cell death in the CCL4- or APAP-challenged mouse liver or Tm-treated hepatocytes. In contrast, pharmaceutical blockade of eukaryotic initiation factor 2α (eIF2α) or genetical ablation of C/EBP homologous protein (CHOP) restored hepatocyte function in the absence of IL-24. In a clinical setting, patients with acute liver failure manifested a profound decrease of hepatic IL-24 expression, which was associated with disease progression. In conclusion, intrinsic hepatocyte IL-24 maintains ER homeostasis by restricting the eIF2α-CHOP pathway-mediated stress signal, which might be exploited as a bio-index for prognosis or therapeutic intervention in patients with liver injury.

scholarly journals ATR-101, a Selective and Potent Inhibitor of Acyl-CoA Acyltransferase 1, Induces Apoptosis in H295R Adrenocortical Cells and in the Adrenal Cortex of Dogs

Endocrinology ◽  
2016 ◽  
Vol 157 (5) ◽  
pp. 1775-1788 ◽  
Author(s):  
Christopher R. LaPensee ◽  
Jacqueline E. Mann ◽  
William E. Rainey ◽  
Valentina Crudo ◽  
Stephen W. Hunt ◽  
...  
Keyword(s):  
Cell Death ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Adrenal Cortex ◽  
Caspase 3 ◽  
Potent Inhibitor ◽  
Adrenocortical Cell ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

Abstract ATR-101 is a novel, oral drug candidate currently in development for the treatment of adrenocortical cancer. ATR-101 is a selective and potent inhibitor of acyl-coenzyme A:cholesterol O-acyltransferase 1 (ACAT1), an enzyme located in the endoplasmic reticulum (ER) membrane that catalyzes esterification of intracellular free cholesterol (FC). We aimed to identify mechanisms by which ATR-101 induces adrenocortical cell death. In H295R human adrenocortical carcinoma cells, ATR-101 decreases the formation of cholesteryl esters and increases FC levels, demonstrating potent inhibition of ACAT1 activity. Caspase-3/7 levels and terminal deoxynucleotidyl transferase 2′-deoxyuridine 5′-triphosphate nick end labeled-positive cells are increased by ATR-101 treatment, indicating activation of apoptosis. Exogenous cholesterol markedly potentiates the activity of ATR-101, suggesting that excess FC that cannot be adequately esterified increases caspase-3/7 activation and subsequent cell death. Inhibition of calcium release from the ER or the subsequent uptake of calcium by mitochondria reverses apoptosis induced by ATR-101. ATR-101 also activates multiple components of the unfolded protein response, an indicator of ER stress. Targeted knockdown of ACAT1 in an adrenocortical cell line mimicked the effects of ATR-101, suggesting that ACAT1 mediates the cytotoxic effects of ATR-101. Finally, in vivo treatment of dogs with ATR-101 decreased adrenocortical steroid production and induced cellular apoptosis that was restricted to the adrenal cortex. Together, these studies demonstrate that inhibition of ACAT1 by ATR-101 increases FC, resulting in dysregulation of ER calcium stores that result in ER stress, the unfolded protein response, and ultimately apoptosis.

scholarly journals Interferon signaling suppresses the unfolded protein response and induces cell death in hepatocytes accumulating hepatitis B surface antigen

2021 ◽  
Vol 17 (5) ◽  
pp. e1009228
Author(s):  
Ian Baudi ◽  
Masanori Isogawa ◽  
Federica Moalli ◽  
Masaya Onishi ◽  
Keigo Kawashima ◽  
...  
Keyword(s):  
Cell Death ◽  
Liver Injury ◽  
Hepatitis B ◽  
Transgenic Mice ◽  
Er Stress ◽  
Hepatitis B Surface Antigen ◽  
Chimeric Mice ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

Virus infection, such as hepatitis B virus (HBV), occasionally causes endoplasmic reticulum (ER) stress. The unfolded protein response (UPR) is counteractive machinery to ER stress, and the failure of UPR to cope with ER stress results in cell death. Mechanisms that regulate the balance between ER stress and UPR are poorly understood. Type 1 and type 2 interferons have been implicated in hepatic flares during chronic HBV infection. Here, we examined the interplay between ER stress, UPR, and IFNs using transgenic mice that express hepatitis B surface antigen (HBsAg) (HBs-Tg mice) and humanized-liver chimeric mice infected with HBV. IFNα causes severe and moderate liver injury in HBs-Tg mice and HBV infected chimeric mice, respectively. The degree of liver injury is directly correlated with HBsAg levels in the liver, and reduction of HBsAg in the transgenic mice alleviates IFNα mediated liver injury. Analyses of total gene expression and UPR biomarkers’ protein expression in the liver revealed that UPR is induced in HBs-Tg mice and HBV infected chimeric mice, indicating that HBsAg accumulation causes ER stress. Notably, IFNα administration transiently suppressed UPR biomarkers before liver injury without affecting intrahepatic HBsAg levels. Furthermore, UPR upregulation by glucose-regulated protein 78 (GRP78) suppression or low dose tunicamycin alleviated IFNα mediated liver injury. These results suggest that IFNα induces ER stress-associated cell death by reducing UPR. IFNγ uses the same mechanism to exert cytotoxicity to HBsAg accumulating hepatocytes. Collectively, our data reveal a previously unknown mechanism of IFN-mediated cell death. This study also identifies UPR as a potential target for regulating ER stress-associated cell death.

scholarly journals Translational and posttranslational regulation of XIAP by eIF2α and ATF4 promotes ER stress–induced cell death during the unfolded protein response

2014 ◽  
Vol 25 (9) ◽  
pp. 1411-1420 ◽  
Author(s):  
Nobuhiko Hiramatsu ◽  
Carissa Messah ◽  
Jaeseok Han ◽  
Matthew M. LaVail ◽  
Randal J. Kaufman ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Protein Misfolding ◽  
Down Regulation ◽  
Unfolded Protein ◽  
Activity Loss ◽  
The Unfolded Protein Response ◽  
Protein Response

Endoplasmic reticulum (ER) protein misfolding activates the unfolded protein response (UPR) to help cells cope with ER stress. If ER homeostasis is not restored, UPR promotes cell death. The mechanisms of UPR-mediated cell death are poorly understood. The PKR-like endoplasmic reticulum kinase (PERK) arm of the UPR is implicated in ER stress–induced cell death, in part through up-regulation of proapoptotic CCAAT/enhancer binding protein homologous protein (CHOP). Chop−/− cells are partially resistant to ER stress–induced cell death, and CHOP overexpression alone does not induce cell death. These findings suggest that additional mechanisms regulate cell death downstream of PERK. Here we find dramatic suppression of antiapoptosis XIAP proteins in response to chronic ER stress. We find that PERK down-regulates XIAP synthesis through eIF2α and promotes XIAP degradation through ATF4. Of interest, PERK's down-regulation of XIAP occurs independently of CHOP activity. Loss of XIAP leads to increased cell death, whereas XIAP overexpression significantly enhances resistance to ER stress–induced cell death, even in the absence of CHOP. Our findings define a novel signaling circuit between PERK and XIAP that operates in parallel with PERK to CHOP induction to influence cell survival during ER stress. We propose a “two-hit” model of ER stress–induced cell death involving concomitant CHOP up-regulation and XIAP down-regulation both induced by PERK.

Hsp90 Inhibitors Deliver a Death Signal Via the Endoplasmic Reticulum Stress Pathway in Myeloma.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 848-848
Author(s):  
Emma L. Davenport ◽  
Hannah Moore ◽  
Alan Dunlop ◽  
Paul Workman ◽  
Gareth J. Morgan ◽  
...  
Keyword(s):  
Cell Death ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Plasma Cells ◽  
Myeloma Cell ◽  
Misfolded Protein ◽  
Hsp90 Inhibitors ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

Abstract Immunoglobulin production by plasma cells both defines them functionally and also provides a differential target for the therapy of their malignant counterparts. Plasma cells producing high levels of paraprotein are dependent upon the unfolded protein response (UPR) and chaperone proteins to ensure correct protein folding and cell survival. We have evaluated a strategy aimed at manipulating the UPR response to deliver a novel death signal in myeloma. In order to study the apoptotic effects of the disruption of the UPR, a panel of myeloma cell lines were treated with the ER stress inducers (thapsigargin (TG) a Ca2+-ATPase inhibitor and tunicamycin (TM) an N-linked glycosylation inhibitor); the HSP90 inhibitors, 17-AAG and radicicol; and the proteasome inhibitor bortezomib, which disrupts misfolded protein disposal. The presence of misfolded proteins in the ER is detected by a complex of proteins embedded within the membrane comprised of BiP, PERK, IRE-1 and ATF6, each of which has distinct downstream effects that are mediated by their release from the complex and activation of the UPR. Treatment with TG and TM led to the activation of all three branches of the UPR as demonstrated by early splicing of XBP1 to XBP1s indicative of IRE1 activation, PERK activation as measured by transcriptional upregulation of CHOP (7-22 fold) and ATF6 splicing. 17-AAG was also capable of inducing splicing of XBP1 and the induction of CHOP (30 fold) whereas bortezomib resulted in induction of CHOP (25 fold) and minimal, late onset splicing of XBP1. Following treatment with all the drugs expression levels of BiP mRNA were upregulated (3-10 fold), however due to high basal levels of BiP protein we were unable to detect any further rises in this protein. The ER-resident HSP90 analogue, Grp94, underwent minimal transcriptional upregulation (2–3 fold) in response to HSP90 inhibitors but larger responses were noted following treatment with TM and TG (3–5 fold). HSP90 protein expression remained constant following exposure to all drugs. In contrast a time-dependent upregulation of the anti-apoptotic HSP70 was noted in response to 17-AAG, radicicol and bortezomib treatment; TG and TM failed to affect levels of HSP70. Levels of the transcript of EDEM1, an ER stress inducible membrane protein that accelerates the degradation of misfolded protein in the ER by strengthening the ERAD machinery, were induced by all drugs with an increase in the transcript levels of between 2 and 4 fold after 24 hours. All drugs were capable of inhibiting proliferation as demonstrated by MTT assay. In addition TG, bortezomib, 17AAG and radicicol also induced myeloma cell death as demonstrated by trypan blue and Annexin V/PI staining. A distinct pattern of activation of caspases in response to the drugs was also established. Bortezomib activated both the intrinsic (caspases 9 and 3) and the extrinsic (caspases 8 and 3) caspase pathways, whilst 17-AAG appears to mediate cell death via the intrinsic pathway alone. In contrast, TM and TG failed to activate either the extrinsic or intrinsic pathways within 24 hours and within this time frame appeared to induce cell death by a caspase-independent mechanism. In conclusion as well as inducing apoptosis via the intrinsic caspase death pathway, HSP90 inhibitors also induce myeloma cell death via ER stress and the UPR death pathway. Our results confirm that the unfolded protein response is an exciting new pathway that can be therapeutically targeted in myeloma.

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