scholarly journals The ATF6β-calreticulin axis promotes neuronal survival under endoplasmic reticulum stress and excitotoxicity

2021 ◽  
Author(s):  
Dinh Thi Nguyen ◽  
Thuong Manh Le ◽  
Tsuyoshi Hattori ◽  
Mika Takarada-Iemata ◽  
Hiroshi Ishii ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Hippocampal Neurons ◽  
Neuronal Survival ◽  
Binding Capacity ◽  
Critical Role ◽  
Er Stress Response ◽  
The Central Nervous System ◽  
The Brain

AbstractWhile ATF6α plays a central role in the endoplasmic reticulum (ER) stress response, the function of ATF6β is largely unknown. Here, we demonstrate that ATF6β is highly expressed in the hippocampus of the brain, and specifically regulates the expression of calreticulin, a molecular chaperone in the ER with a high Ca2+-binding capacity. Calreticulin expression was reduced to ~50% in the central nervous system of Atf6b−/− mice, and restored by ATF6β. Analysis using cultured hippocampal neurons revealed that ATF6β deficiency reduced Ca2+ stores in the ER and enhanced ER stress-induced death, which was rescued by ATF6β, calreticulin, Ca2+-modulating reagents such as BAPTA-AM and 2-APB, and ER stress inhibitor salubrinal. In vivo, kainate-induced neuronal death was enhanced in hippocampi of Atf6b−/− and Calr+/− mice, and restored by 2-APB and salubrinal. These results suggest that the ATF6β-calreticulin axis plays a critical role in the neuronal survival by improving Ca2+ homeostasis under ER stress.

scholarly journals The ATF6β-calreticulin axis promotes neuronal survival under endoplasmic reticulum stress and excitotoxicity

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Dinh Thi Nguyen ◽  
Thuong Manh Le ◽  
Tsuyoshi Hattori ◽  
Mika Takarada-Iemata ◽  
Hiroshi Ishii ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Hippocampal Neurons ◽  
Neuronal Survival ◽  
Binding Capacity ◽  
Er Stress Response ◽  
Intracellular Ca ◽  
The Central Nervous System ◽  
The Brain

AbstractWhile ATF6α plays a central role in the endoplasmic reticulum (ER) stress response, the function of its paralogue ATF6β remains elusive, especially in the central nervous system (CNS). Here, we demonstrate that ATF6β is highly expressed in the hippocampus of the brain, and specifically regulates the expression of calreticulin (CRT), a molecular chaperone in the ER with a high Ca2+-binding capacity. CRT expression was reduced to ~ 50% in the CNS of Atf6b−/− mice under both normal and ER stress conditions. Analysis using cultured hippocampal neurons revealed that ATF6β deficiency reduced Ca2+ stores in the ER and enhanced ER stress-induced death. The higher levels of death in Atf6b−/− neurons were recovered by ATF6β and CRT overexpressions, or by treatment with Ca2+-modulating reagents such as BAPTA-AM and 2-APB, and with an ER stress inhibitor salubrinal. In vivo, kainate-induced neuronal death was enhanced in the hippocampi of Atf6b−/− and Calr+/− mice, and restored by administration of 2-APB and salubrinal. These results suggest that the ATF6β-CRT axis promotes neuronal survival under ER stress and excitotoxity by improving intracellular Ca2+ homeostasis.

scholarly journals The ATF6β-Calreticulin Axis Promotes Neuronal Survival Under Endoplasmic Reticulum Stress and Excitotoxicity

2021 ◽  
Author(s):  
Dinh Thi Nguyen ◽  
Thuong Manh Le ◽  
Tsuyoshi Hattori ◽  
Mika Takarada-Iemata ◽  
Hiroshi Ishii ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Hippocampal Neurons ◽  
Neuronal Survival ◽  
Binding Capacity ◽  
Er Stress Response ◽  
Intracellular Ca ◽  
The Central Nervous System ◽  
The Brain

Abstract While ATF6α plays a central role in the endoplasmic reticulum (ER) stress response, the function of its homologue ATF6β remains elusive, especially in the central nervous system (CNS). Here, we demonstrate that ATF6β is highly expressed in the hippocampus of the brain, and specifically regulates the expression of calreticulin (CRT), a molecular chaperone in the ER with a high Ca2+-binding capacity. CRT expression was reduced to ~ 50% in the CNS of Atf6b−/− mice under both normal and ER stress conditions. Analysis using cultured hippocampal neurons revealed that ATF6β deficiency reduced Ca2+ stores in the ER and enhanced ER stress-induced death. The higher levels of death in Atf6b−/− neurons were recovered by ATF6β and CRT overexpressions, or by treatment with Ca2+-modulating reagents such as BAPTA-AM and 2-APB, and with an ER stress inhibitor salubrinal. In vivo, kainate-induced neuronal death was enhanced in the hippocampi of Atf6b−/− and Calr+/− mice, and restored by administration of 2-APB and salubrinal. These results suggest that the ATF6β-CRT axis promotes neuronal survival under ER stress and excitotoxity by improving intracellular Ca2+ homeostasis.

scholarly journals NOD1/NOD2 and RIP2 Regulate Endoplasmic Reticulum Stress-Induced Inflammation during Chlamydia Infection

mBio ◽  
2020 ◽  
Vol 11 (3) ◽  
Author(s):  
Oanh H. Pham ◽  
Bokyung Lee ◽  
Jasmine Labuda ◽  
A. Marijke Keestra-Gounder ◽  
Mariana X. Byndloss ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Stress Response ◽  
Inflammatory Response ◽  
Endoplasmic Reticulum Stress ◽  
Er Stress ◽  
Young Women ◽  
The United States ◽  
Chlamydia Infection ◽  
Er Stress Response

ABSTRACT The inflammatory response to Chlamydia infection is likely to be multifactorial and involve a variety of ligand-dependent and -independent recognition pathways. We previously reported the presence of NOD1/NOD2-dependent endoplasmic reticulum (ER) stress-induced inflammation during Chlamydia muridarum infection in vitro, but the relevance of this finding to an in vivo context is unclear. Here, we examined the ER stress response to in vivo Chlamydia infection. The induction of interleukin 6 (IL-6) production after systemic Chlamydia infection correlated with expression of ER stress response genes. Furthermore, when tauroursodeoxycholate (TUDCA) was used to inhibit the ER stress response, an increased bacterial burden was detected, suggesting that ER stress-driven inflammation can contribute to systemic bacterial clearance. Mice lacking both NOD1 and NOD2 or RIP2 exhibited slightly higher systemic bacterial burdens after infection with Chlamydia. Overall, these data suggest a model where RIP2 and NOD1/NOD2 proteins link ER stress responses with the induction of Chlamydia-specific inflammatory responses. IMPORTANCE Understanding the initiation of the inflammatory response during Chlamydia infection is of public health importance given the impact of this disease on young women in the United States. Many young women are chronically infected with Chlamydia but are asymptomatic and therefore do not seek treatment, leaving them at risk of long-term reproductive harm due to inflammation in response to infection. Our manuscript explores the role of the endoplasmic reticulum stress response pathway initiated by an innate receptor in the development of this inflammation.

scholarly journals Regulation of Adipsin Expression by Endoplasmic Reticulum Stress in Adipocytes

Biomolecules ◽  
2020 ◽  
Vol 10 (2) ◽  
pp. 314
Author(s):  
Ka-Young Ryu ◽  
Eon Ju Jeon ◽  
Jaechan Leem ◽  
Jae-Hyung Park ◽  
Hochan Cho
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Peroxisome Proliferator ◽  
Adipose Tissues ◽  
Peroxisome Proliferator Activated Receptor ◽  
Er Stress Response ◽  
Stress Markers ◽  
Transcriptional Reprogramming

Adpsin is an adipokine that stimulates insulin secretion from β-cells and improves glucose tolerance. Its expression has been found to be markedly reduced in obese animals. However, it remains unclear what factors lead to downregulation of adipsin in the context of obesity. Endoplasmic reticulum (ER) stress response is activated in various tissues under obesity-related conditions and can induce transcriptional reprogramming. Therefore, we aimed to investigate the relationship between adipsin expression and ER stress in adipose tissues during obesity. We observed that obese mice exhibited decreased levels of adipsin in adipose tissues and serum and increased ER stress markers in adipose tissues compared to lean mice. We also found that ER stress suppressed adipsin expression via adipocytes-intrinsic mechanisms. Moreover, the ER stress-mediated downregulation of adipsin was at least partially attributed to decreased expression of peroxisome proliferator-activated receptor γ (PPARγ), a key transcription factor in the regulation of adipocyte function. Finally, treatment with chemical chaperones recovered the ER stress-mediated downregulation of adipsin and PPARγ in vivo and in vitro. Our findings suggest that activated ER stress in adipose tissues is an important cause of the suppression of adipsin expression in the context of obesity.

scholarly journals Liver-specific deletion of protein tyrosine phosphatase (PTP) 1B improves obesity- and pharmacologically induced endoplasmic reticulum stress

2011 ◽  
Vol 438 (2) ◽  
pp. 369-378 ◽  
Author(s):  
Abdelali Agouni ◽  
Nimesh Mody ◽  
Carl Owen ◽  
Alicja Czopek ◽  
Derek Zimmer ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Stress Response ◽  
Insulin Sensitivity ◽  
Er Stress ◽  
Protein Tyrosine Phosphatase ◽  
Mouse Liver ◽  
Tyrosine Phosphatase ◽  
Er Stress Response

Obesity is associated with induction of the ER (endoplasmic reticulum)-stress response signalling and insulin resistance. PTP1B (protein tyrosine phosphatase 1B) is a major regulator of adiposity and insulin sensitivity. The aim of the present study was to investigate the role of L-PTP1B (liver-specific PTP1B) in chronically HFD (high-fat diet) and pharmacologically induced (tunicamycin and thapsigargin) ER-stress response signalling in vitro and in vivo. We assessed the effects of ER-stress response induction on hepatic PTP1B expression, and consequences of hepatic-PTP1B deficiency, in cells and mouse liver, on components of ER-stress response signalling. We found that PTP1B protein and mRNA expression levels were up-regulated in response to acute and/or chronic ER stress, in vitro and in vivo. Silencing PTP1B in hepatic cell lines or mouse liver (L-PTP1B−/−) protected against induction of pharmacologically induced and/or obesity-induced ER stress. The HFD-induced increase in CHOP (CCAAT/enhancer-binding protein homologous protein) and BIP (binding immunoglobulin protein) mRNA levels were partially inhibited, whereas ATF4 (activated transcription factor 4), GADD34 (growth-arrest and DNA-damage-inducible protein 34), GRP94 (glucose-regulated protein 94), ERDJ4 (ER-localized DnaJ homologue) mRNAs and ATF6 protein cleavage were completely suppressed in L-PTP1B−/− mice relative to control littermates. L-PTP1B−/− mice also had increased nuclear translocation of spliced XBP-1 (X box-binding protein-1) via increased p85α binding. We demonstrate that the ER-stress response and L-PTP1B expression are interlinked in obesity- and pharmacologically induced ER stress and this may be one of the mechanisms behind improved insulin sensitivity and lower lipid accumulation in L-PTP1B−/− mice.

scholarly journals PRMT1 suppresses ATF4-mediated endoplasmic reticulum response in cardiomyocytes

2019 ◽  
Vol 10 (12) ◽  
Author(s):  
Myong-Ho Jeong ◽  
Hyeon-Ju Jeong ◽  
Byeong-Yun Ahn ◽  
Jung-Hoon Pyun ◽  
Ilmin Kwon ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Stress Response ◽  
Er Stress ◽  
Regulatory Mechanism ◽  
Critical Role ◽  
Mechanistic Study ◽  
Stress Signaling ◽  
Deficient Mutant ◽  
Er Stress Response

AbstractEndoplasmic reticulum (ER) stress signaling plays a critical role in the control of cell survival or death. Persistent ER stress activates proapoptotic pathway involving the ATF4/CHOP axis. Although accumulating evidences support its important contribution to cardiovascular diseases, but its mechanism is not well characterized. Here, we demonstrate a critical role for PRMT1 in the control of ER stress in cardiomyocytes. The inhibition of PRMT1 augments tunicamycin (TN)-triggered ER stress response in cardiomyocytes while PRMT1 overexpression attenuates it. Consistently, PRMT1 null hearts show exacerbated ER stress and cell death in response to TN treatment. Interestingly, ATF4 depletion attenuates the ER stress response induced by PRMT1 inhibition. The methylation-deficient mutant of ATF4 with the switch of arginine 239 to lysine exacerbates ER stress accompanied by enhanced levels of proapoptotic cleaved Caspase3 and phosphorylated-γH2AX in response to TN. The mechanistic study shows that PRMT1 modulates the protein stability of ATF4 through methylation. Taken together, our data suggest that ATF4 methylation on arginine 239 by PRMT1 is a novel regulatory mechanism for protection of cardiomyocytes from ER stress-induced cell death.

Co-Treatment with Panobinostat Enhances Bortezomib-Induced Unfolded Protein Response, Endoplasmic Reticulum Stress and Apoptosis of Human Mantle Cell Lymphoma Cells

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 887-887 ◽  
Author(s):  
Rekha Rao ◽  
Warren Fiskus ◽  
Yonghua Yang ◽  
Rajeshree Joshi ◽  
Pravina Fernandez ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Stress Response ◽  
Er Stress ◽  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
Unfolded Protein ◽  
Er Stress Response ◽  
Mantle Cell ◽  
Protein Response

Abstract The 26S proteasome inhibitor bortezomib (BZ), which increases intracellular unfolded protein levels and toxicity through endoplasmic reticulum (ER) stress response, was shown to have a single agent activity in relapsed mantle cell lymphoma (MCL). Here we have determined that treatment with hydroxamic acid analogue (HA) pan-histone deacetylase (HDAC) inhibitor (HDI), e.g., panobinostat (LBH589, Novartis Pharmaceuticals Inc) induces the CDK inhibitors p21 and p27, and attenuates the levels of c-Myc, CDK4 and cyclin D1 in the cultured (Jeko-1, MO-2058 and Granta-519) and in primary patient-derived MCL cells. In a dose-dependent manner, panobinostat also induced Bax and Bak, and attenuated Bcl-xL, XIAP, survivin, AKT and c-Raf levels, resulting in growth inhibition and apoptosis of MCL cells. We have previously demonstrated that HDAC6 deacetylates heat shock protein (hsp) 90, as well as shuttles and sequesters misfolded and polyubiquitylated proteins into the protective perinuclear aggresome.. By inhibiting HDAC6, panobinostat (10 to 50 nM) induced acetylation of hsp90 in MCL cells. This inhibited the ATP binding and co-chaperone association, and abrogated the chaperone function of hsp90 for the MCL- relevant, hsp90 client proteins, e.g., cyclin D1, CDK4, c-Raf and AKT in the cultured and primary MCL cells. Panobinostat mediated inhibition of HDAC6 abrogated formation of the aggresome and augmented endoplasmic reticulum (ER)-based unfolded protein response (UPR). Treatment of MCL cells with BZ induced the formation of aggresome (as detected by confocal immuno-fluorescence microscopy and electron microscopy), as well as induced UPR and ER stress response. The latter was associated with BZ-mediated increased levels of GRP78, the spliced form of XBP1 (XBP1s) and p-eIF2α protein. As compared to the control siRNA treated cells, knockdown of GRP78 by siRNA markedly increased BZ-induced CHOP and Noxa levels and significantly augmented BZ-induced apoptosis of cultured MCL cells. Co-treatment of MCL cells with panobinostat abrogated BZ-induced aggresome formation, decreased the levels of ATF4, XBP1s and p-eIF2α, as well as increased the levels of CHOP, Noxa and GADD34. Ultrastructural analysis of Jeko-1 cells also revealed that co-treatment with panobinostat and BZ showed pronounced ER dilatation compared to panobinostat treatment alone, suggestive of enhanced ER stress. Higher and persistent CHOP and Noxa levels suggested a protracted ER-stress, associated with synergistic increase in apoptosis of MCL but not normal CD34+ bone marrow progenitor cells (p < 0.01). Conversely, knockdown of CHOP levels by siRNA significantly inhibited panobinostat and BZ-induced cell death of MCL cells. Results of ongoing in vivo studies of panobinostat and/or BZ in the NOD/SCID mouse xenograft model of Jeko-1 MCL cells will be presented. These findings strongly support further in vivo evaluation of the efficacy of the combination of panobinostat with BZ against human MCL. Additionally, the findings create the rationale to develop targeted knockdown of GRP78 as a novel strategy to augment lethal ER stress due to panobinostat and BZ and resulting activity against MCL cells.

scholarly journals Nck-dependent Activation of Extracellular Signal-regulated Kinase-1 and Regulation of Cell Survival during Endoplasmic Reticulum Stress

2004 ◽  
Vol 15 (9) ◽  
pp. 4248-4260 ◽  
Author(s):  
Duc Thang Nguyên ◽  
Sem Kebache ◽  
Ali Fazel ◽  
Hetty N. Wong ◽  
Sarah Jenna ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Protein Kinase ◽  
Er Stress ◽  
Cell Survival ◽  
Mapk Pathway ◽  
Critical Role ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal

In response to stress, the endoplasmic reticulum (ER) signaling machinery triggers the inhibition of protein synthesis and up-regulation of genes whose products are involved in protein folding, cell cycle exit, and/or apoptosis. We demonstrate that the misfolding agents azetidine-2-carboxylic acid (Azc) and tunicamycin initiate signaling from the ER, resulting in the activation of Jun-N-terminal kinase, p44MAPK/extracellular signal-regulated kinase-1 (ERK-1), and p38MAPK through IRE1α-dependent mechanisms. To characterize the ER proximal signaling events involved, immuno-isolated ER membranes from rat fibroblasts treated with ER stress inducers were used to reconstitute the activation of the stress-activated protein kinase/mitogen-activate protein kinase (MAPK) pathways in vitro. This allowed us to demonstrate a role for the SH2/SH3 domain containing adaptor Nck in ERK-1 activation after Azc treatment. We also show both in vitro and in vivo that under basal conditions ER-associated Nck represses ERK-1 activation and that upon ER stress this pool of Nck dissociates from the ER membrane to allow ERK-1 activation. Moreover, under the same conditions, Nck-null cells elicit a stronger ERK-1 activation in response to Azc stress, thus, correlating with an enhanced survival phenotype. These data delineate a novel mechanism for the regulation of ER stress signaling to the MAPK pathway and demonstrate a critical role for Nck in ER stress and cell survival.

scholarly journals Prion-Associated Neurodegeneration Causes Both Endoplasmic Reticulum Stress and Proteasome Impairment in a Murine Model of Spontaneous Disease

2021 ◽  
Vol 22 (1) ◽  
pp. 465
Author(s):  
Alicia Otero ◽  
Marina Betancor ◽  
Hasier Eraña ◽  
Natalia Fernández Borges ◽  
José J. Lucas ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Prion Disease ◽  
Murine Model ◽  
Secretory Pathway ◽  
Prion Diseases ◽  
Early Stages ◽  
Gfp Reporter ◽  
The Central Nervous System

Prion diseases are a group of neurodegenerative disorders that can be spontaneous, familial or acquired by infection. The conversion of the prion protein PrPC to its abnormal and misfolded isoform PrPSc is the main event in the pathogenesis of prion diseases of all origins. In spontaneous prion diseases, the mechanisms that trigger the formation of PrPSc in the central nervous system remain unknown. Several reports have demonstrated that the accumulation of PrPSc can induce endoplasmic reticulum (ER) stress and proteasome impairment from the early stages of the prion disease. Both mechanisms lead to an increment of PrP aggregates in the secretory pathway, which could explain the pathogenesis of spontaneous prion diseases. Here, we investigate the role of ER stress and proteasome impairment during prion disorders in a murine model of spontaneous prion disease (TgVole) co-expressing the UbG76V-GFP reporter, which allows measuring the proteasome activity in vivo. Spontaneously prion-affected mice showed a significantly higher accumulation of the PKR-like ER kinase (PERK), the ER chaperone binding immunoglobulin protein (BiP/Grp78), the ER protein disulfide isomerase (PDI) and the UbG76V-GFP reporter than age-matched controls in certain brain areas. The upregulation of PERK, BiP, PDI and ubiquitin was detected from the preclinical stage of the disease, indicating that ER stress and proteasome impairment begin at early stages of the spontaneous disease. Strong correlations were found between the deposition of these markers and neuropathological markers of prion disease in both preclinical and clinical mice. Our results suggest that both ER stress and proteasome impairment occur during the pathogenesis of spontaneous prion diseases.

scholarly journals FBXO6-Mediated Ubiquitination and Degradation of Ero1L Inhibits Endoplasmic Reticulum Stress-Induced Apoptosis

2016 ◽  
Vol 39 (6) ◽  
pp. 2501-2508 ◽  
Author(s):  
Xi Chen ◽  
Lang-Huan Duan ◽  
Peng-cheng Luo ◽  
Gang Hu ◽  
Xin Yu ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Critical Role ◽  
Dependent Manner ◽  
Ubiquitin E3 Ligase ◽  
The Stability ◽  
Induced Apoptosis ◽  
F Box Protein ◽  
Protein Disulfide

Background/Aims: FBXO6 is the substrate recognition component of a Skp1-Cullin1-F-box protein (SCF) ubiquitin E3 ligase complex, recognizing the chitobiose in unfolded N-glycoprotein to target glycoproteins for polyubiquitination and degradation. Although how FBXO6 recognizes glycoprotein has been fully investigated, the ubiquitination substrates of FBXO6 remain largely unknown. Previously, we have systematically identified the glycoproteins that interact with FBXO6 in an N-glycan dependent manner by LC/MS spectrum and confirmed the interaction between FBXO6 and glycosylated Ero1L, a protein disulfide oxidase in endoplasmic reticulum (ER). Methods: The relationship between endogenous Ero1L and exogenous Flag-FBXO6 were determined by Western blot. In vivo ubiquitination assay was used to detect the direct effect of FBXO6 in the regulation of Ero1L. Both CCK8 and FACS assays were used to determine the apoptosis ratio of cells after treatments. Results: Ero1L is a ubiquitination substrate of FBXO6. FBXO6 mediates the degradation of Ero1L through a ubiquitylation-dependent pathway. Overexpression of FBXO6 increased the polyubiquitination and decreased the stability of Ero1L, whereas inhibition of FBXO6 prolonged the half-life of Ero1L. Functionally, we show that FBXO6 inhibits ER stress-induced apoptosis by modulating the protein level of Ero1L. Conclusion: Collectively, our results demonstrate FBXO6 as a functional E3 ubiquitin ligase for Ero1L that plays a critical role in inhibiting ER stress-induced apoptosis.

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