Silencing of the ER and Integrative Stress Responses in the Liver of Mice with Error-Prone Translation

Translational errors frequently arise during protein synthesis, producing misfolded and dysfunctional proteins. Chronic stress resulting from translation errors may be particularly relevant in tissues that must synthesize and secrete large amounts of secretory proteins. Here, we studied the proteostasis networks in the liver of mice that express the Rps2-A226Y ribosomal ambiguity (ram) mutation to increase the translation error rate across all proteins. We found that Rps2-A226Y mice lack activation of the eIF2 kinase/ATF4 pathway, the main component of the integrated stress response (ISR), as well as the IRE1 and ATF6 pathways of the ER unfolded protein response (ER-UPR). Instead, we found downregulation of chronic ER stress responses, as indicated by reduced gene expression for lipogenic pathways and acute phase proteins, possibly via upregulation of Sirtuin-1. In parallel, we observed activation of alternative proteostasis responses, including the proteasome and the formation of stress granules. Together, our results point to a concerted response to error-prone translation to alleviate ER stress in favor of activating alternative proteostasis mechanisms, most likely to avoid cell damage and apoptotic pathways, which would result from persistent activation of the ER and integrated stress responses.

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Proteostasis In The Endoplasmic Reticulum: Road to Cure

Cancers ◽

10.3390/cancers11111793 ◽

2019 ◽

Vol 11 (11) ◽

pp. 1793 ◽

Cited By ~ 7

Author(s):

Nam ◽

Jeon

Keyword(s):

Endoplasmic Reticulum ◽

Er Stress ◽

Unfolded Protein Response ◽

Protein Quality ◽

Tumor Development ◽

Therapeutic Interventions ◽

Secretory Proteins ◽

Unfolded Protein ◽

Stress Signals ◽

Protein Response

The endoplasmic reticulum (ER) is an interconnected organelle that is responsible for the biosynthesis, folding, maturation, stabilization, and trafficking of transmembrane and secretory proteins. Therefore, cells evolve protein quality-control equipment of the ER to ensure protein homeostasis, also termed proteostasis. However, disruption in the folding capacity of the ER caused by a large variety of pathophysiological insults leads to the accumulation of unfolded or misfolded proteins in this organelle, known as ER stress. Upon ER stress, unfolded protein response (UPR) of the ER is activated, integrates ER stress signals, and transduces the integrated signals to relive ER stress, thereby leading to the re-establishment of proteostasis. Intriguingly, severe and persistent ER stress and the subsequently sustained unfolded protein response (UPR) are closely associated with tumor development, angiogenesis, aggressiveness, immunosuppression, and therapeutic response of cancer. Additionally, the UPR interconnects various processes in and around the tumor microenvironment. Therefore, it has begun to be delineated that pharmacologically and genetically manipulating strategies directed to target the UPR of the ER might exhibit positive clinical outcome in cancer. In the present review, we summarize recent advances in our understanding of the UPR of the ER and the UPR of the ER–mitochondria interconnection. We also highlight new insights into how the UPR of the ER in response to pathophysiological perturbations is implicated in the pathogenesis of cancer. We provide the concept to target the UPR of the ER, eventually discussing the potential of therapeutic interventions for targeting the UPR of the ER for cancer treatment.

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Targeting Endoplasmic Reticulum Stress as an Effective Treatment for Alcoholic Pancreatitis

Biomedicines ◽

10.3390/biomedicines10010108 ◽

2022 ◽

Vol 10 (1) ◽

pp. 108

Author(s):

Hui Li ◽

Wen Wen ◽

Jia Luo

Keyword(s):

Endoplasmic Reticulum ◽

Er Stress ◽

Effective Treatment ◽

Stress Responses ◽

Treatment Strategies ◽

Alcoholic Pancreatitis ◽

Excessive Alcohol Consumption ◽

Unfolded Protein ◽

Novel Therapeutic Strategies ◽

Protein Response

Pancreatitis and alcoholic pancreatitis are serious health concerns with an urgent need for effective treatment strategies. Alcohol is a known etiological factor for pancreatitis, including acute pancreatitis (AP) and chronic pancreatitis (CP). Excessive alcohol consumption induces many pathological stress responses; of particular note is endoplasmic reticulum (ER) stress and adaptive unfolded protein response (UPR). ER stress results from the accumulation of unfolded/misfolded protein in the ER and is implicated in the pathogenesis of alcoholic pancreatitis. Here, we summarize the possible mechanisms by which ER stress contributes to alcoholic pancreatitis. We also discuss potential approaches targeting ER stress and UPR in developing novel therapeutic strategies for the disease.

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GAS1Deficient Enhances UPR Activity inSaccharomyces cerevisiae

BioMed Research International ◽

10.1155/2019/1238581 ◽

2019 ◽

Vol 2019 ◽

pp. 1-12

Author(s):

Hong-jing Cui ◽

Xin-gang Cui ◽

Xia Jing ◽

Yuan Yuan ◽

Ya-qin Chen ◽

...

Keyword(s):

Er Stress ◽

Stress Responses ◽

Molecular Mechanisms ◽

Yeast Cells ◽

Unfolded Protein ◽

Proliferation Ability ◽

The Unfolded Protein Response ◽

Protein Response ◽

Cycle Regulation ◽

Wild Type Yeast

Beta-1,3-glucanosyltransferase (Gas1p) plays important roles in cell wall biosynthesis and morphogenesis and has been implicated in DNA damage responses and cell cycle regulation in fungi. Yeast Gas1p has also been reported to participate in endoplasmic reticulum (ER) stress responses. However, the precise roles and molecular mechanisms through which Gas1p affects these responses have yet to be elucidated. In this study, we constructedGAS1-deficient (gas1Δ) andGAS1-overexpressing (GAS1 OE) yeast strains and observed that thegas1Δstrain exhibited a decreased proliferation ability and a shorter replicative lifespan (RLS), as well as enhanced activity of the unfolded protein response (UPR) in the absence of stress. However, under the high-tunicamycin-concentration (an ER stress-inducing agent; 1.0 μg/mL) stress, thegas1Δyeast cells exhibited an increased proliferation ability compared with the wild-type yeast strain. In addition, our findings demonstrated thatIRE1andHAC1(two upstream modulators of the UPR) are required for the survival ofgas1Δyeast cells under the tunicamycin stress. On the other hand, we provided evidence that theGAS1overexpression caused an obvious sensitivity to the low-tunicamycin-concentration (0.25 μg/mL). Collectively, our results indicate that Gas1p plays an important role in the ageing and ER stress responses in yeast.

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Multilevel regulation of endoplasmic reticulum stress responses in plants: where old roads and new paths meet

Journal of Experimental Botany ◽

10.1093/jxb/erz487 ◽

2019 ◽

Vol 71 (5) ◽

pp. 1659-1667 ◽

Cited By ~ 10

Author(s):

Taiaba Afrin ◽

Danish Diwan ◽

Katrina Sahawneh ◽

Karolina Pajerowska-Mukhtar

Keyword(s):

Endoplasmic Reticulum ◽

Stress Response ◽

Er Stress ◽

Stress Responses ◽

Translational Control ◽

Protein Quality ◽

Unfolded Protein ◽

Transcriptional Gene Regulation ◽

The Unfolded Protein Response ◽

Protein Response

Abstract The sessile lifestyle of plants requires them to cope with a multitude of stresses in situ. In response to diverse environmental and intracellular cues, plant cells respond by massive reprogramming of transcription and translation of stress response regulators, many of which rely on endoplasmic reticulum (ER) processing. This increased protein synthesis could exceed the capacity of precise protein quality control, leading to the accumulation of unfolded and/or misfolded proteins that triggers the unfolded protein response (UPR). Such cellular stress responses are multilayered and executed in different cellular compartments. Here, we will discuss the three main branches of UPR signaling in diverse eukaryotic systems, and describe various levels of ER stress response regulation that encompass transcriptional gene regulation by master transcription factors, post-transcriptional activities including cytoplasmic splicing, translational control, and multiple post-translational events such as peptide modifications and cleavage. In addition, we will discuss the roles of plant ER stress sensors in abiotic and biotic stress responses and speculate on the future prospects of engineering these signaling events for heightened stress tolerance.

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Tauroursodeoxycholic acid reduces endoplasmic reticulum stress, acinar cell damage, and systemic inflammation in acute pancreatitis

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00483.2010 ◽

2011 ◽

Vol 301 (5) ◽

pp. G773-G782 ◽

Cited By ~ 50

Author(s):

Ersin Seyhun ◽

Antje Malo ◽

Claus Schäfer ◽

Christopher A. Moskaluk ◽

Ralf-Thorsten Hoffmann ◽

...

Keyword(s):

Acute Pancreatitis ◽

Endoplasmic Reticulum ◽

Er Stress ◽

Stress Responses ◽

Cell Damage ◽

Binding Protein ◽

Edema Formation ◽

Tauroursodeoxycholic Acid ◽

Caspase 12

In acute pancreatitis, endoplasmic reticulum (ER) stress prompts an accumulation of malfolded proteins inside the ER, initiating the unfolded protein response (UPR). Because the ER chaperone tauroursodeoxycholic acid (TUDCA) is known to inhibit the UPR in vitro, this study examined the in vivo effects of TUDCA in an acute experimental pancreatitis model. Acute pancreatitis was induced in Wistar rats using caerulein, with or without prior TUDCA treatment. UPR components were analyzed, including chaperone binding protein (BiP), phosphorylated protein kinase-like ER kinase (pPERK), X-box binding protein (XBP)-1, phosphorylated c-Jun NH2-terminal kinase (pJNK), CCAAT/enhancer binding protein homologues protein, and caspase 12 and 3 activation. In addition, pancreatitis biomarkers were measured, such as serum amylase, trypsin activation, edema formation, histology, and the inflammatory reaction in pancreatic and lung tissue. TUDCA treatment reduced intracellular trypsin activation, edema formation, and cell damage, while leaving amylase levels unaltered. The activation of myeloperoxidase was clearly reduced in pancreas and lung. Furthermore, TUDCA prevented caerulein-induced BiP upregulation, reduced XBP-1 splicing, and caspase 12 and 3 activation. It accelerated the downregulation of pJNK. In controls without pancreatitis, TUDCA showed cytoprotective effects including pPERK signaling and activation of downstream targets. We concluded that ER stress responses activated in acute pancreatitis are grossly attenuated by TUDCA. The chaperone reduced the UPR and inhibited ER stress-associated proapoptotic pathways. TUDCA has a cytoprotective potential in the exocrine pancreas. These data hint at new perspectives for an employment of chemical chaperones, such as TUDCA, in prevention of acute pancreatitis.

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A Complex Scenario and Underestimated Challenge: The Tumor Microenvironment, ER Stress, and Cancer Treatment

Current Medicinal Chemistry ◽

10.2174/0929867325666180117110259 ◽

2018 ◽

Vol 25 (21) ◽

pp. 2465-2502 ◽

Cited By ~ 12

Author(s):

Oleg I. Chen ◽

Yaroslav P. Bobak ◽

Oleh V. Stasyk ◽

Leoni A. Kunz-Schughart

Keyword(s):

Er Stress ◽

Stress Responses ◽

Tumor Hypoxia ◽

Cancer Treatments ◽

Comprehensive Overview ◽

Unfolded Protein ◽

The Unfolded Protein Response ◽

Complex Scenario ◽

The Impact

The paradoxical role of ER stress in malignant diseases is only just being unraveled and remains incompletely understood. A particular challenge is the complex interplay between spaciotemporal and locoregional microenvironmental constraints in solid tumors and stress responses upon treatment; thus, the potential for new combinatorial therapeutic options to foster the coincidence of ER stress-related deadly events is likely to be underestimated. Without claiming this review to be complete, we present a comprehensive overview of the signaling mechanisms associated with the unfolded protein response (UPR) and the molecular link to cell survival and death mechanisms. We (i) delineate the mechanistic scenario and outcome of the UPR; (ii) discuss the role of ER stress in cancer development and progression; (iii) highlight the impact of various environmental conditions and stress stimuli, such as nutrient limitation and tumor hypoxia, in this context; and (iv) attempt to shed some light on the putative link between DNA damage, irradiation, and ER stress to emphasize the potential of therapeutic targeting of ER stress pathways for combined cancer treatments.

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Ipomoeassin-F disrupts multiple aspects of secretory protein biogenesis

Scientific Reports ◽

10.1038/s41598-021-91107-4 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Peristera Roboti ◽

Sarah O’Keefe ◽

Kwabena B. Duah ◽

Wei Q. Shi ◽

Stephen High

Keyword(s):

Stress Responses ◽

Secretory Pathway ◽

Secretory Protein ◽

Secretory Proteins ◽

Unfolded Protein ◽

Cellular Stress Responses ◽

Protein Entry ◽

Protein Response ◽

Er Homeostasis

AbstractThe Sec61 complex translocates nascent polypeptides into and across the membrane of the endoplasmic reticulum (ER), providing access to the secretory pathway. In this study, we show that Ipomoeassin-F (Ipom-F), a selective inhibitor of protein entry into the ER lumen, blocks the in vitro translocation of certain secretory proteins and ER lumenal folding factors whilst barely affecting others such as albumin. The effects of Ipom-F on protein secretion from HepG2 cells are twofold: reduced ER translocation combined, in some cases, with defective ER lumenal folding. This latter issue is most likely a consequence of Ipom-F preventing the cell from replenishing its ER lumenal chaperones. Ipom-F treatment results in two cellular stress responses: firstly, an upregulation of stress-inducible cytosolic chaperones, Hsp70 and Hsp90; secondly, an atypical unfolded protein response (UPR) linked to the Ipom-F-mediated perturbation of ER function. Hence, although levels of spliced XBP1 and CHOP mRNA and ATF4 protein increase with Ipom-F, the accompanying increase in the levels of ER lumenal BiP and GRP94 seen with tunicamycin are not observed. In short, although Ipom-F reduces the biosynthetic load of newly synthesised secretory proteins entering the ER lumen, its effects on the UPR preclude the cell restoring ER homeostasis.

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Salicylic acid-independent role of NPR1 is required for protection from proteotoxic stress in the plant endoplasmic reticulum

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1802254115 ◽

2018 ◽

Vol 115 (22) ◽

pp. E5203-E5212 ◽

Cited By ~ 19

Author(s):

Ya-Shiuan Lai ◽

Luciana Renna ◽

John Yarema ◽

Cristina Ruberti ◽

Sheng Yang He ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Salicylic Acid ◽

Er Stress ◽

Stress Responses ◽

Unfolded Protein ◽

Redox Activation ◽

Genetic Level ◽

The Unfolded Protein Response ◽

Protein Response

The unfolded protein response (UPR) is an ancient signaling pathway designed to protect cells from the accumulation of unfolded and misfolded proteins in the endoplasmic reticulum (ER). Because misregulation of the UPR is potentially lethal, a stringent surveillance signaling system must be in place to modulate the UPR. The major signaling arms of the plant UPR have been discovered and rely on the transcriptional activity of the transcription factors bZIP60 and bZIP28 and on the kinase and ribonuclease activity of IRE1, which splices mRNA to activate bZIP60. Both bZIP28 and bZIP60 modulate UPR gene expression to overcome ER stress. In this study, we demonstrate at a genetic level that the transcriptional role of bZIP28 and bZIP60 in ER-stress responses is antagonized by nonexpressor of PR1 genes 1 (NPR1), a critical redox-regulated master regulator of salicylic acid (SA)-dependent responses to pathogens, independently of its role in SA defense. We also establish that the function of NPR1 in the UPR is concomitant with ER stress-induced reduction of the cytosol and translocation of NPR1 to the nucleus where it interacts with bZIP28 and bZIP60. Our results support a cellular role for NPR1 as well as a model for plant UPR regulation whereby SA-independent ER stress-induced redox activation of NPR1 suppresses the transcriptional role of bZIP28 and bZIP60 in the UPR.

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The Cross-Links of Endoplasmic Reticulum Stress, Autophagy, and Nurodegeneration in Parkinson’s Disease

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2021.691881 ◽

2021 ◽

Vol 13 ◽

Author(s):

Haigang Ren ◽

Wanqing Zhai ◽

Xiaojun Lu ◽

Guanghui Wang

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Endoplasmic Reticulum ◽

Er Stress ◽

Substantia Nigra Pars Compacta ◽

Cellular Processes ◽

Unfolded Protein ◽

Cross Links ◽

Main Component ◽

Protein Response

Parkinson’s disease (PD) is the most common neurodegenerative movement disorder, and it is characterized by the selective loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc), as well as the presence of intracellular inclusions with α-synuclein as the main component in surviving DA neurons. Emerging evidence suggests that the imbalance of proteostasis is a key pathogenic factor for PD. Endoplasmic reticulum (ER) stress-induced unfolded protein response (UPR) and autophagy, two major pathways for maintaining proteostasis, play important roles in PD pathology and are considered as attractive therapeutic targets for PD treatment. However, although ER stress/UPR and autophagy appear to be independent cellular processes, they are closely related to each other. In this review, we focused on the roles and molecular cross-links between ER stress/UPR and autophagy in PD pathology. We systematically reviewed and summarized the most recent advances in regulation of ER stress/UPR and autophagy, and their cross-linking mechanisms. We also reviewed and discussed the mechanisms of the coexisting ER stress/UPR activation and dysregulated autophagy in the lesion regions of PD patients, and the underlying roles and molecular crosslinks between ER stress/UPR activation and the dysregulated autophagy in DA neurodegeneration induced by PD-associated genetic factors and PD-related neurotoxins. Finally, we indicate that the combined regulation of ER stress/UPR and autophagy would be a more effective treatment for PD rather than regulating one of these conditions alone.

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ADP-ribose Transferase PARP16 Mediated-unfolded Protein Response Contributes to Neuronal Cell Damage in Cerebral Ischemia/Reperfusion

10.21203/rs.3.rs-823416/v1 ◽

2021 ◽

Author(s):

Jinghuan Wang ◽

zhenghua Su ◽

wen Zhong ◽

haibi Su ◽

Jie Xu ◽

...

Keyword(s):

Ischemic Stroke ◽

Er Stress ◽

Unfolded Protein Response ◽

Cortical Neurons ◽

Cell Damage ◽

Transmembrane Protein ◽

Ischemia Reperfusion ◽

Neuronal Cell ◽

Unfolded Protein ◽

Protein Response

Abstract Ischemic stroke is known to cause the accumulation of misfolded proteins and loss of calcium homeostasis leading to impairment of endoplasmic reticulum (ER) function and activating the unfolded protein response (UPR). PARP16 is the only an active ADP-ribosyl transferase known tail-anchored ER transmembrane protein with a cytosolic catalytic domain. Here, we find PARP16 is highly expressed in ischemic cerebral hemisphere and Oxygen-glucose deprivation (OGD)-treated immortalized hippocampal neuroblasts HT22 cells. Using adeno-associated virus-mediated knockdown PARP16 mice, we find knockdown PARP16 decreases infarct demarcations and has a better neurological outcome after ischemic stroke. Our data indicate PARP16 overexpression promotes ER stress-mediated cell damage in primary cortical neurons, in turn, knockdown PARP16 decreases ER stress and neuronal death caused by OGD. Furthermore, PARP16 functions mechanistically as ADP-ribosyltransferase to modulate the level of ribosylation of the corresponding PERK and IRE1α arm of the UPR, and that such modification is required for activation of PERK and IRE1α. Indeed, pharmacological stimulation of the UPR using Brefeldin A counteracts knockdown of PARP16-mediated neuronal protection in OGD. On other hand, when an ER inhibitor Tauroursodeoxycholic acid present, permit more obvious protection and inactivation of PERK and IRF1α caused by knockdown of PARP16. In conclusion, PARP16 plays a crucial role in post-ischemic UPR and the knockdown of PARP16 alleviates brain injury after ischemic stroke. The rationale of this study is to explore the potentials of the PARP16-PERK/IRE1α axis as a target for neuronal survival in ischemic stroke.

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