bims-unfpre Biomed News
on Unfolded protein response
Issue of 2023–02–05
seven papers selected by
Susan Logue, University of Manitoba
  1. EVA1A regulates hematopoietic stem cell regeneration via ER-mitochondria mediated apoptosis.
  2. The Bcl-2 family protein Bid interacts with the ER stress sensor IRE1 to differentially modulate its RNase activity.
  3. Phosphorylation of EIF2S1 (eukaryotic translation initiation factor 2 subunit alpha) is indispensable for nuclear translocation of TFEB and TFE3 during ER stress.
  4. RASSF1 is identified by transcriptome coordination analysis as a target of ATF4.
  5. Endoplasmic reticulum stress inhibition ameliorated WFS1 expression alterations and reduced pancreatic islets' insulin secretion induced by high-fat diet in rats.
  6. HERV1-env Induces Unfolded Protein Response Activation in Autoimmune Liver Disease: A Potential Mechanism for Regulatory T Cell Dysfunction.
  7. Advanced glycation end products induce skeletal muscle atrophy and insulin resistance via activating ROS-mediated ER stress PERK/FOXO1 signaling.
  1. Cell Death Dis. 2023 Jan 30. 14(1): 71
    EVA1A regulates hematopoietic stem cell regeneration via ER-mitochondria mediated apoptosis.
    Bo Liu, Yuanyuan Zhou, Qiaofeng Wu, Yuting Fu, Xianli Zhang, Zhenkun Wang, Weiwei Yi, Hu Wang, Zhiyang Chen, Zhangfa Song, Wei Xiong, Yugang Qiu, Weifeng He, Zhenyu Ju.
      Excessive protein synthesis upon enhanced cell proliferation frequently results in an increase of unfolded or misfolded proteins. During hematopoietic regeneration, to replenish the hematopoietic system, hematopoietic stem cells (HSCs) are activated and undergo a rapid proliferation. But how the activated HSCs respond to the proliferation pressure is still ambiguous; The proper control of the functional reservoir in the activated HSCs remains poorly understood. Here, we show a significant upregulation of EVA1A protein associated with the increase of ER stress during hematopoietic regeneration. Deletion of Eva1a significantly enhances the regeneration capacity of HSCs by inhibiting the ER stress-induced apoptosis. Mechanistically, the expression of EVA1A protein was upregulated by CHOP, and thereby promoted the ER-mitochondria interlinking via MCL1, which resulted in mitochondria-mediated apoptosis. These findings reveal a pathway for ER stress responses of HSCs by the EVA1A mediated apoptosis, which play an important role in HSCs regeneration.
    DOI:  https://doi.org/10.1038/s41419-023-05559-9
  2. FEBS Lett. 2023 Feb 01.
    The Bcl-2 family protein Bid interacts with the ER stress sensor IRE1 to differentially modulate its RNase activity.
    Samirul Bashir, Mariam Banday, Ozaira Qadri, Debnath Pal, Arif Bashir, Nazia Hilal, Mohammad Altaf, Khalid Majid Fazili.
      IRE1 is a transmembrane signaling protein that activates the unfolded protein response under endoplasmic reticulum stress. IRE1 is endowed with kinase and endoribonuclease activities. The ribonuclease activity of IRE1 can switch substrate specificities to carry out atypical splicing of Xbp1 mRNA or trigger degradation of specific mRNAs. The mechanisms regulating the distinct ribonuclease activities of IRE1 have yet to be fully understood. Here, we report the Bcl-2 family protein Bid as a novel recruit of the IRE1 complex, which directly interacts with the cytoplasmic domain of IRE1. Bid binding to IRE1 leads to a decrease in IRE1 phosphorylation in a way that it can only perform Xbp1 splicing while mRNA degradation activity is repressed. The RNase outputs of IRE1 have been found to regulate the homeostatic-apoptotic switch. This study thus provides insight into IRE1-mediated cell survival.
    Keywords:  Bid; IRE1; RNase activity; UPRosome; phosphorylation
    DOI:  https://doi.org/10.1002/1873-3468.14593
  3. Autophagy. 2023 Jan 31.
    Phosphorylation of EIF2S1 (eukaryotic translation initiation factor 2 subunit alpha) is indispensable for nuclear translocation of TFEB and TFE3 during ER stress.
    Thao Thi Dang, Mi-Jeong Kim, Yoon Young Lee, Hien Thi Le, Kook Hwan Kim, Somi Nam, Seung Hwa Hyun, Hong Lim Kim, Su Wol Chung, Hun Taeg Chung, Eek-Hoon Jho, Hiderou Yoshida, Kyoungmi Kim, Chan Young Park, Myung-Shik Lee, Sung Hoon Back.
      There are diverse links between macroautophagy/autophagy pathways and unfolded protein response (UPR) pathways under endoplasmic reticulum (ER) stress conditions to restore ER homeostasis. Phosphorylation of EIF2S1/eIF2α is an important mechanism that can regulate all three UPR pathways through transcriptional and translational reprogramming to maintain cellular homeostasis and overcome cellular stresses. In this study, to investigate the roles of EIF2S1 phosphorylation in regulation of autophagy during ER stress, we used EIF2S1 phosphorylation-deficient (A/A) cells in which residue 51 was mutated from serine to alanine. A/A cells exhibited defects in several steps of autophagic processes (such as autophagosome and autolysosome formation) that are regulated by the transcriptional activities of the autophagy master transcription factors TFEB and TFE3 under ER stress conditions. EIF2S1 phosphorylation was required for nuclear translocation of TFEB and TFE3 during ER stress. In addition, EIF2AK3/PERK, PPP3/calcineurin-mediated dephosphorylation of TFEB and TFE3, and YWHA/14-3-3 dissociation were required for their nuclear translocation, but were insufficient to induce their nuclear retention during ER stress. Overexpression of the activated ATF6/ATF6α form, XBP1s, and ATF4 differentially rescued defects of TFEB and TFE3 nuclear translocation in A/A cells during ER stress. Consequently, overexpression of the activated ATF6 or TFEB form more efficiently rescued autophagic defects, although XBP1s and ATF4 also displayed an ability to restore autophagy in A/A cells during ER stress. Our results suggest that EIF2S1 phosphorylation is important for autophagy and UPR pathways, to restore ER homeostasis and reveal how EIF2S1 phosphorylation connects UPR pathways to autophagy.
    Keywords:  ATF6; EIF2S1 phosphorylation; ER stress; TFEB; autophagy; nuclear translocation; phosphorylation TFE3; transcription factor E3; transcription factor EB
    DOI:  https://doi.org/10.1080/15548627.2023.2173900
  4. FEBS Open Bio. 2023 Feb 01.
    RASSF1 is identified by transcriptome coordination analysis as a target of ATF4.
    Youwen Zhang, Kim-Tuyen Huynh-Dam, Xiaokai Ding, Vitali Sikirzhytski, Chang-Uk Lim, Eugenia Broude, Hippokratis Kiaris.
      Evaluation of gene co-regulation is a powerful approach for revealing regulatory associations between genes and predicting biological function, especially in genetically diverse samples. Here, we applied this strategy to identify transcripts that are co-regulated with unfolded protein response (UPR) genes in cultured fibroblasts from outbred deer mice. Our analyses showed that the transcriptome associated with RASSF1, a tumor suppressor involved in cell cycle regulation and not previously linked to UPR, is highly correlated with the transcriptome of several UPR-related genes, such as BiP/GRP78, DNAJB9, GRP94, ATF4, DNAJC3 and CHOP/DDIT3. Conversely, gene ontology analyses for genes co-regulated with RASSF1 predicted a previously unreported involvement in UPR-associated apoptosis. Bioinformatic analyses indicated the presence of ATF4 binding sites in the RASSF1 promoter, which were shown to be operational using chromatin immunoprecipitation. Reporter assays revealed that the RASSF1 promoter is responsive to ATF4, while ablation of RASSF1 mitigated expression of the ATF4 effector BBC3 and abrogated tunicamycin-induced apoptosis. Collectively, these results implicate RASSF1 in the regulation of ER stress-associated apoptosis downstream of ATF4. They also illustrate the power of gene coordination analysis in predicting biological functions and revealing regulatory associations between genes.
    Keywords:  ATF4; ER Stress; RASSF1; Transcriptome Coordination Analysis; Unfolded Protein Response
    DOI:  https://doi.org/10.1002/2211-5463.13569
  5. Sci Rep. 2023 Feb 01. 13(1): 1860
    Endoplasmic reticulum stress inhibition ameliorated WFS1 expression alterations and reduced pancreatic islets' insulin secretion induced by high-fat diet in rats.
    Fateme Binayi, Javad Fahanik-Babaei, Mina Salimi, Farzaneh Eskandari, Mohammad Sahraei, Ali Ghorbani Ranjbary, Rasoul Ghasemi, Mehdi Hedayati, Fariba Khodagholi, Afsaneh Eliassi, Homeira Zardooz.
      Endoplasmic reticulum (ER) stress is involved in the development of glucose homeostasis impairment. When ER stress occurs, the unfolded protein response (UPR) is activated to cope with it. One of the UPR components is WFS1 (Wolfram syndrome 1), which plays important roles in ER homeostasis and pancreatic islets glucose-stimulated insulin secretion (GSIS). Accordingly and considering that feeding high-fat food has a major contribution in metabolic disorders, this study aimed to investigate the possible involvement of pancreatic ER stress in glucose metabolism impairment induced by feeding high-fat diet (HFD) in male rats. After weaning, the rats were divided into six groups, and fed on normal diet and HFD for 20 weeks, then 4-phenyl butyric acid (4-PBA, an ER stress inhibitor) was administered. Subsequently, in all groups, after performing glucose tolerance test, the animals were dissected and their pancreases were removed to extract ER, islets isolation and assessment of GSIS. Moreover, the pancreatic ER stress [binding of immunoglobulin protein (BIP) and enhancer-binding protein homologous protein (CHOP)] and oxidative stress [malondialdehyde (MDA), glutathione (GSH) and catalase] biomarkers as well as WFS1 expression level were evaluated. HFD decreased pancreatic WFS1 protein and GSH levels, and enhanced pancreatic catalase activity, MDA content, BIP and CHOP protein and mRNA levels as well as Wfs1 mRNA amount. Accordingly, it increased BIP, CHOP and WFS1 protein levels in the extracted ER of pancreas. In addition, the HFD caused glucose intolerance, and decreased the islets' GSIS and insulin content. However, 4-PBA administration restored the alterations. It seems that, HFD consumption through inducing pancreatic ER stress, altered WFS1 expression levels, reduced the islets' GSIS and insulin content and finally impaired glucose homeostasis.
    DOI:  https://doi.org/10.1038/s41598-023-28329-1
  6. J Immunol. 2023 Feb 01. pii: ji2100186. [Epub ahead of print]
    HERV1-env Induces Unfolded Protein Response Activation in Autoimmune Liver Disease: A Potential Mechanism for Regulatory T Cell Dysfunction.
    Kumar Subramanian, Saikat Paul, Andrew Libby, Jordan Patterson, Adam Arterbery, James Knight, Christopher Castaldi, Guilin Wang, Yaron Avitzur, Mercedes Martinez, Steve Lobritto, Yanhong Deng, Gan Geliang, Alexander Kroemer, Thomas Fishbein, Andrew Mason, Margarita Dominguez-Villar, Malaiyalam Mariappan, Udeme D Ekong.
      Regulatory T cells (Tregs) are not terminally differentiated but can acquire effector properties. Here we report an increased expression of human endogenous retrovirus 1 (HERV1-env) proteins in Tregs of patients with de novo autoimmune hepatitis and autoimmune hepatitis, which induces endoplasmic reticulum (ER) stress. HERV1-env-triggered ER stress activates all three branches (IRE1, ATF6, and PERK) of the unfolded protein response (UPR). Our coimmunoprecipitation studies show an interaction between HERV1-env proteins and the ATF6 branch of the UPR. The activated form of ATF6α activates the expression of RORC and STAT3 by binding to promoter sequences and induces IL-17A production. Silencing of HERV1-env results in recovery of Treg suppressive function. These findings identify ER stress and UPR activation as key factors driving Treg plasticity (species: human).
    DOI:  https://doi.org/10.4049/jimmunol.2100186
  7. Am J Physiol Endocrinol Metab. 2023 Feb 01.
    Advanced glycation end products induce skeletal muscle atrophy and insulin resistance via activating ROS-mediated ER stress PERK/FOXO1 signaling.
    Haixia Du, Yanpeng Ma, Xiqiang Wang, Yong Zhang, Ling Zhu, Shuang Shi, Shuo Pan, Zhongwei Liu.
      Skeletal muscle atrophy is often found in patients with type 2 diabetes mellitus (T2DM) which is characterized with insulin resistance. As the largest tissue in the body, skeletal muscle plays important roles in insulin resistance. Advanced glycation end products (AGEs) are representative toxic metabolites and associated with multiple pathophysiologic changes of T2DM. In this study, we investigated whether AGEs could exacerbate skeletal muscle atrophy and its related insulin resistance. Mice were exposed to AGEs. Forkhead box O1 (FOXO1) was silenced by a constructed viral vector carrying siRNA. Skeletal muscle atrophy was evaluated by H&E, oil red O, myosin skeletal heavy chain (MHC) and laminin immunofluorescent stains. Reactive oxygen species (ROS) generation was assessed by DHE stain. Western blotting was used to evaluate protein expression and phosphorylation. Insulin resistance was monitored by insulin tolerance test (ITT) and glucose infusion rate (GIR). Mice exposed to AGEs showed insulin resistance which was evidenced by reduced ITT and GIR. H&E and MHC immunofluorescent stains suggested reduced cross-sectional muscle fiber area. Laminin immunofluorescent and Oil red O stains indicated increased intramuscular fibrosis and lipid deposit respectively. AGEs exposure induced ROS generation, increased phosphorylation of protein kinase RNA-like endoplasmic reticulum kinase (PERK) and FOXO1, facilitated FOXO1 nuclear translocation and elevated expression of muscle atrophy F-box (MAFbx) in gastrocnemius muscle. foxo1 silencing significantly suppressed skeletal muscle atrophy and insulin resistance without affecting ROS production. AGEs exacerbated skeletal muscle atrophy and insulin resistance by activating PERK/FOXO1 signaling pathway in skeletal muscle.
    Keywords:  Advanced glycation end products; Atrophy; Endoplasmic reticulum stress; Insulin resistance; Skeletal muscle
    DOI:  https://doi.org/10.1152/ajpendo.00218.2022
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