Endoplasmic reticulum stress and protein degradation in chronic liver disease

Xia, Siwei; Wang, Zhimin; Sun, Sumin; Su, Ying; Li, Zhanghao; Shao, Jiangjuan; Tan, Shanzhong; Chen, Anping; Wang, Shijun; Zhang, Zili; Zhang, Feng; Zheng, Shizhong

doi:10.1016/j.phrs.2020.105218

Cited by 73 publications

(48 citation statements)

References 137 publications

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“…In addition, ER stress can enhance cancer cell immune evasion and promote recurrence and metastasis by affecting the tumor microenvironment (TME) [35,36]. ER stress-mediated UPR induces autophagy via IRE1α, PERK and ATF6 signaling channels and stimulates vascular endothelial growth factor(VEGF)secretion by macrophages, thereby promoting vasculogenesis in TME [37,38]. Studies to date have shown that ER stress plays a substantial role in regulating tumor cell fate through altered metabolic status and has emerged as a novel signaling target for the treatment of HCC.…”

Section: Discussionmentioning

confidence: 99%

Endoplasmic Reticulum Stress-related Classification for Prognosis Prediction in Hepatocellular Carcinoma

Zhang

2021

Preprint

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Background: Cancer cells under ER stress are common in hepatocellular carcinoma (HCC) and ER stress is strongly associated with poor prognosis. The aim of this study was to discover credible biomarkers for predicting prognosis of HCC based on ER stress-related genes (ERSRGs). Methods: Univariate Cox regression was performed to calculate the association between ERSRGs and survival outcomes of HCC patients in TCGA. Then LASSO-Cox regression strategy and stepwise Cox regression examination were performed to investigate the quality and establish the prognostic characteristics associated with prognosis. Finally, the model was subsequently validated in two additional independent HCC cohorts.Results: A novel seven-gene prognostic risk model based on ERSRGs was constructed and exhibited superior accuracy in forecasting the survival outcomes and 1-, 2-, 3- year survival rate of HCC patients. qRT-PCR was performed to validate the prognostic risk model in an independent clinical cohort containing 59 HCC patients and the results revealed that this signature had a good prognostic performance. Moreover, we found ER stress could affect the immune microenvironment in HCC and immune checkpoint inhibitors (ICIs) treatment was more effective for patients in high-risk subgroup. In addition, we identified 103 tumor-sensitive drugs in the CellMiner database that may be available for the treatment of HCC patients targeting ER stress and constructed a nomogram combining ER stress-related feature, TNM stage, age and gender. Conclusions: Our seven genetic risk model associated with ER stress can accurately predict survival outcome in HCC patients and facilitate the selection of the best individualized treatment targeting ER stress.

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Section: Discussionmentioning

confidence: 99%

Endoplasmic Reticulum Stress-related Classification for Prognosis Prediction in Hepatocellular Carcinoma

Zhang

2021

Preprint

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“…The concomitant depletion of ER calcium stores hampers the activity of calcium-dependent local chaperones, like calnexin, and induces an aberrant accumulation of unfolded/misfolded protein within the organelle lumen that defines the ER stress [32]. The cell, in return, engages the UPR network that integrates signals about the chronicity and severity of the insult and coordinates the activation patterns of PERK, ATF6, and IRE1a effector signaling to determine cell fate [14,33]. For instance, prolonged ER stress sustains over time the up-regulated activation of PERK-a Ser/Thr protein kinase of which the catalytic core shares a substantial homology to eIF2A and phosphorylates eiF2α at the serine 51 residue.…”

Section: Discussionmentioning

confidence: 99%

Role of Hydrogen Sulfide and 3-Mercaptopyruvate Sulfurtransferase in the Regulation of the Endoplasmic Reticulum Stress Response in Hepatocytes

2020

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It is estimated that over 1.5 billion people suffer from various forms of chronic liver disease worldwide. The emerging prevalence of metabolic syndromes and alcohol misuse, along with the lack of disease-modifying agents for the therapy of many severe liver conditions predicts that chronic liver disease will continue to be a major problem in the future. Better understanding of the underlying pathogenetic mechanisms and identification of potential therapeutic targets remains a priority. Herein, we explored the potential role of the 3-mercaptopyruvate sulfurtransferase/hydrogen sulfide (H2S) system in the regulation of the endoplasmic reticulum (ER) stress and of its downstream processes in the immortalized hepatic cell line HepG2 in vitro. ER stress suppressed endogenous H2S levels and pharmacological supplementation of H2S with sodium hydrogen sulfide (NaHS) mitigated many aspects of ER stress, culminating in improved cellular bioenergetics and prevention of autophagic arrest, thereby switching cells’ fate towards survival. Genetic silencing of 3-MST or pharmacological inhibition of the key enzymes involved in hepatocyte H2S biosynthesis exacerbated many readouts related to ER-stress or its downstream functional responses. Our findings implicate the 3-MST/H2S system in the intracellular network that governs proteostasis and ER-stress adaptability in hepatocytes and reinforce the therapeutic potential of pharmacological H2S supplementation.

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“…Protein degradation is an important step in processing ER stress. The major protein degradation system includes the ubiquitin-proteasome system (UPS) and the autophagic-lysosomal system (ALS), which can selectively degrade aberrant protein fragments ( Xia et al, 2020 ). In most cases, micromolecules and short-lived soluble proteins are retrotranslocated into the cytosol, ubiquitinated, and then degraded by the proteasomes in the ERAD system.…”

Section: Endoplasmic Reticulum Stress Response and Protein Degradationmentioning

confidence: 99%

Endoplasmic Reticulum Quality Control in Immune Cells

Jiang

Tao

Chen

et al. 2021

Front. Cell Dev. Biol.

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The endoplasmic reticulum quality control (ERQC) system, including endoplasmic reticulum-associated degradation (ERAD), the unfolded protein response (UPR), and autophagy, presides over cellular protein secretion and maintains proteostasis in mammalian cells. As part of the immune system, a variety of proteins are synthesized and assembled correctly for the development, activation, and differentiation of immune cells, such as dendritic cells (DCs), macrophages, myeloid-derived-suppressor cells (MDSCs), B lymphocytes, T lymphocytes, and natural killer (NK) cells. In this review, we emphasize the role of the ERQC in these immune cells, and also discuss how the imbalance of ER homeostasis affects the immune response, thereby suggesting new therapeutic targets for immunotherapy.

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Endoplasmic reticulum stress and protein degradation in chronic liver disease

Cited by 73 publications

References 137 publications

Endoplasmic Reticulum Stress-related Classification for Prognosis Prediction in Hepatocellular Carcinoma

Endoplasmic Reticulum Stress-related Classification for Prognosis Prediction in Hepatocellular Carcinoma

Role of Hydrogen Sulfide and 3-Mercaptopyruvate Sulfurtransferase in the Regulation of the Endoplasmic Reticulum Stress Response in Hepatocytes

Endoplasmic Reticulum Quality Control in Immune Cells

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