bims-unfpre Biomed News
on Unfolded protein response
Issue of 2020–10–04
thirteen papers selected by
Susan Logue, University of Manitoba
  1. Alleviating chronic ER stress by p38-Ire1-Xbp1 pathway and insulin-associated autophagy in C. elegans neurons.
  2. Pancreatic Cancer Cells Require the Transcription Factor MYRF to Maintain ER Homeostasis.
  3. The integrated stress response in pulmonary disease.
  4. Inactivation of the Caenorhabditis elegans RNF-5 E3 ligase promotes IRE-1-independent ER functions.
  5. Glucose-regulated protein 78 (GRP78) as a potential novel biomarker and therapeutic target in multiple myeloma.
  6. Endoplasmic reticulum stress and protein degradation in chronic liver disease.
  7. Snf1 AMPK positively regulates ER-phagy via expression control of Atg39 autophagy receptor in yeast ER stress response.
  8. COPII mitigates ER stress by promoting formation of ER whorls.
  9. Nna1 gene deficiency triggers Purkinje neuron death by tubulin hyperglutamylation and ER dysfunction.
  10. Prolonged Lipid Accumulation in Cultured Primary Human Hepatocytes Rather Leads to ER Stress than Oxidative Stress.
  11. Regulation of Cellular Immunity by Activating Transcription Factor 4.
  12. A pathogen branched-chain amino acid catabolic pathway subverts host survival by impairing energy metabolism and the mitochondrial UPR.
  13. Proteostasis Disturbances and Inflammation in Neurodegenerative Diseases.
  1. PLoS Genet. 2020 Sep 28. 16(9): e1008704
    Alleviating chronic ER stress by p38-Ire1-Xbp1 pathway and insulin-associated autophagy in C. elegans neurons.
    Liying Guan, Zhigao Zhan, Yongzhi Yang, Yue Miao, Xun Huang, Mei Ding.
      ER stress occurs in many physiological and pathological conditions. However, how chronic ER stress is alleviated in specific cells in an intact organism is an outstanding question. Here, overexpressing the gap junction protein UNC-9 (Uncoordinated) in C. elegans neurons triggers the Ire1-Xbp1-mediated stress response in an age-dependent and cell-autonomous manner. The p38 MAPK PMK-3 regulates the chronic stress through IRE-1 phosphorylation. Overexpressing gap junction protein also activates autophagy. The insulin pathway functions through autophagy, but not the transcription of genes encoding ER chaperones, to counteract the p38-Ire1-Xbp1-mediated stress response. Together, these results reveal an intricate cellular regulatory network in response to chronic stress in a subset of cells in multicellular organism.
    DOI:  https://doi.org/10.1371/journal.pgen.1008704
  2. Dev Cell. 2020 Sep 24. pii: S1534-5807(20)30713-9. [Epub ahead of print]
    Pancreatic Cancer Cells Require the Transcription Factor MYRF to Maintain ER Homeostasis.
    Marta Milan, Chiara Balestrieri, Gabriele Alfarano, Sara Polletti, Elena Prosperini, Paola Nicoli, Paola Spaggiari, Alessandro Zerbi, Vincenzo Cirulli, Giuseppe R Diaferia, Gioacchino Natoli.
      Many tumors of endodermal origin are composed of highly secretory cancer cells that must adapt endoplasmic reticulum (ER) activity to enable proper folding of secreted proteins and prevent ER stress. We found that pancreatic ductal adenocarcinomas (PDACs) overexpress the myelin regulatory factor (MYRF), an ER membrane-associated transcription factor (TF) released by self-cleavage. MYRF was expressed in the well-differentiated secretory cancer cells, but not in the poorly differentiated quasi-mesenchymal cells that coexist in the same tumor. MYRF expression was controlled by the epithelial identity TF HNF1B, and it acted to fine-tune the expression of genes encoding highly glycosylated, cysteine-rich secretory proteins, thus preventing ER overload. MYRF-deficient PDAC cells showed signs of ER stress, impaired proliferation, and an inability to form spheroids in vitro, while in vivo they generated highly secretory but poorly proliferating and hypocellular tumors. These data indicate a role of MYRF in the control of ER homeostasis in highly secretory PDAC cells.
    Keywords:  ER stress; MYRF; differentiation; pancreatic cancer; stress response; transcription; tumor heterogeneity; unfolded protein response
    DOI:  https://doi.org/10.1016/j.devcel.2020.09.011
  3. Eur Respir Rev. 2020 Sep 30. pii: 200184. [Epub ahead of print]29(157):
    The integrated stress response in pulmonary disease.
    Giulia Emanuelli, Nikou Nassehzadeh-Tabriz, Nick W Morrell, Stefan J Marciniak.
      The respiratory tract and its resident immune cells face daily exposure to stress, both from without and from within. Inhaled pathogens, including severe acute respiratory syndrome coronavirus 2, and toxins from pollution trigger a cellular defence system that reduces protein synthesis to minimise viral replication or the accumulation of misfolded proteins. Simultaneously, a gene expression programme enhances antioxidant and protein folding machineries in the lung. Four kinases (PERK, PKR, GCN2 and HRI) sense a diverse range of stresses to trigger this "integrated stress response". Here we review recent advances identifying the integrated stress response as a critical pathway in the pathogenesis of pulmonary diseases, including pneumonias, thoracic malignancy, pulmonary fibrosis and pulmonary hypertension. Understanding the integrated stress response provides novel targets for the development of therapies.
    DOI:  https://doi.org/10.1183/16000617.0184-2020
  4. Autophagy. 2020 Sep 26.
    Inactivation of the Caenorhabditis elegans RNF-5 E3 ligase promotes IRE-1-independent ER functions.
    Limor Broday, Orit Adir, Ulrike Bening-Abu-Shach, Shir Arbib, Sivan Henis-Korenblit.
      RNF5 is implicated in ERAD and in negative regulation of macroautophagy/autophagy. To better understand the function of RNF-5 under ER-stress conditions, we studied the ability of Caenorhabditis elegans rnf-5(tm794) mutant animals to cope with stress in the background of impaired UPR machinery. We demonstrate that downregulation of RNF-5 decreased sensitivity to tunicamycin both in wild type and in an ire-1 mutant. Double-mutant rnf-5;ire-1 animals showed increased starvation resistance and extended lifespan when compared to the ire-1 mutant. This partial rescue of ire-1 required functional autophagy. Downregulation of RNF-5 rescued ER maturation defects and protein secretion of a DAF-28::GFP intestinal reporter in the ire-1 background. Proteomics and functional studies revealed an increase in lysosomal protease levels, in the frequency of intestinal lysosomes, and in lysosomal protease activity in rnf-5(tm794) animals. Together, these data suggest that RNF-5 is a negative regulator of ER stress, and that inactivation of RNF-5 promotes IRE-1-independent elevation of ER capacity.
    Keywords:  IRE1; RMA1; RNF5; autophagy, C. elegans ; endoplasmic reticulum; lysosome
    DOI:  https://doi.org/10.1080/15548627.2020.1827778
  5. Expert Rev Hematol. 2020 Sep 29.
    Glucose-regulated protein 78 (GRP78) as a potential novel biomarker and therapeutic target in multiple myeloma.
    Slavisa Ninkovic, Simon J Harrison, Hang Quach.
       INTRODUCTION: Glucose-regulated protein 78 (GRP78) is a stress-inducible molecular chaperone expressed within the endoplasmic reticulum where it acts a master regulator of the unfolded protein response (UPR) pathway. At times of ER stress, activation of the UPR, a multimolecular pathway, limits proteotoxicity induced by misfolded proteins. In malignancies, including multiple myeloma which is characterised by an excessive accumulation of misfolded immunoglobulins, GRP78 expression is increased, with notable translocation of GRP78 to the cell surface. Studies suggest cell surface GRP78 (csGRP78) to be of prognostic significance with emerging evidence that it interacts with a myriad of co-ligands to activate signalling pathways which may promote cell proliferation and survival or apoptosis.
    AREAS COVERED: This review will focus on the role of ER and csGRP78 in physiology and oncogenesis in multiple myeloma, addressing the factors that shift the balance in GRP78 signalling from survival to apoptosis. The role of GRP78 as a potential prognostic biomarker is explored and current therapeutics in development aimed at targeting csGRP78 are addressed. We conducted a PubMed literature search using the key words "GRP78", "multiple myeloma" reviewing studies prior to 2020.
    EXPERT OPINION: Cell surface GRP78 expression is a potential novel prognostic biomarker in myeloma and targeting of csGRP78 is promising and requires further investigation.
    Keywords:  ER stress; biomarker; glucose-regulated protein 78 (GRP78); multiple myeloma; therapeutic target
    DOI:  https://doi.org/10.1080/17474086.2020.1830372
  6. Pharmacol Res. 2020 Sep 29. pii: S1043-6618(20)31526-7. [Epub ahead of print] 105218
    Endoplasmic reticulum stress and protein degradation in chronic liver disease.
    Si-Wei Xia, Zhi-Min Wang, Su-Min Sun, Ying Su, Zhang-Hao Li, Jiang-Juan Shao, Shan-Zhong Tan, An-Ping Chen, Shi-Jun Wang, Zi-Li Zhang, Feng Zhang, Shi-Zhong Zheng.
      Endoplasmic reticulum (ER) stress is easily observed in chronic liver disease, which often causes accumulation of unfolded or misfolded proteins in the ER, leading to unfolded protein response (UPR). Regulating protein degradation is an integral part of UPR to relieve ER stress. The major protein degradation system includes the ubiquitin-proteasome system (UPS) and autophagy. All three arms of UPR triggered in response to ER stress can regulate UPS and autophagy. Accumulated misfolded proteins could activate these arms, and then generate various transcription factors to regulate the expression of UPS-related and autophagy-related genes. The protein degradation process regulated by UPR has great significance in many chronic liver diseases, including non-alcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), viral hepatitis, liver fibrosis, and hepatocellular carcinoma(HCC). In most instances, the degradation of excessive proteins protects cells with ER stress survival from apoptosis. According to the specific functions of protein degradation in chronic liver disease, choosing to promote or inhibit this process is promising as a potential method for treating chronic liver disease.
    Keywords:  3-MA (PubChem CID: 135398661); 4-PBA (PubChem CID: 83242); 4μ8c (PubChem CID: 12934390); Bortezomib (PubChem CID: 387447); Chloroquine (PubChem CID: 2719); GSK2656157 (PubChem CID: 53469059); MG-132 (PubChem CID: 24892475); Rapamycin (PubChem CID: 5284616); Salubrinal (PubChem CID: 5717801); TUDCA (PubChem CID: 9848818); autophagy; chronic liver disease; endoplasmic reticulum stress; ubiquitin-proteasome system; unfolded protein response
    DOI:  https://doi.org/10.1016/j.phrs.2020.105218
  7. PLoS Genet. 2020 Sep 28. 16(9): e1009053
    Snf1 AMPK positively regulates ER-phagy via expression control of Atg39 autophagy receptor in yeast ER stress response.
    Tomoaki Mizuno, Kei Muroi, Kenji Irie.
      Autophagy is a fundamental process responsible for degradation and recycling of intracellular contents. In the budding yeast, non-selective macroautophagy and microautophagy of the endoplasmic reticulum (ER) are caused by ER stress, the circumstance where aberrant proteins accumulate in the ER. The more recent study showed that protein aggregation in the ER initiates ER-selective macroautophagy, referred to as ER-phagy; however, the mechanisms by which ER stress induces ER-phagy have not been fully elucidated. Here, we show that the expression levels of ATG39, encoding an autophagy receptor specific for ER-phagy, are significantly increased under ER-stressed conditions. ATG39 upregulation in ER stress response is mediated by activation of its promoter, which is positively regulated by Snf1 AMP-activated protein kinase (AMPK) and negatively by Mig1 and Mig2 transcriptional repressors. In response to ER stress, Snf1 promotes nuclear export of Mig1 and Mig2. Our results suggest that during ER stress response, Snf1 mediates activation of the ATG39 promoter and consequently facilitates ER-phagy by negatively regulating Mig1 and Mig2.
    DOI:  https://doi.org/10.1371/journal.pgen.1009053
  8. Cell Res. 2020 Sep 28.
    COPII mitigates ER stress by promoting formation of ER whorls.
    Fang Xu, Wanqing Du, Qin Zou, Yuting Wang, Xin Zhang, Xudong Xing, Ying Li, Dachuan Zhang, Huimin Wang, Wenhao Zhang, Xinyao Hu, Xin Liu, Xiaoling Liu, Shaojin Zhang, Jinqiang Yu, Jianhuo Fang, Fajin Li, Ying Zhou, Tieqiang Yue, Na Mi, Haiteng Deng, Peng Zou, Xiaowei Chen, Xuerui Yang, Li Yu.
      Cells mitigate ER stress through the unfolded protein response (UPR). Here, we report formation of ER whorls as an effector mechanism of the ER stress response. We found that strong ER stress induces formation of ER whorls, which contain ER-resident proteins such as the Sec61 complex and PKR-like ER kinase (PERK). ER whorl formation is dependent on PERK kinase activity and is mediated by COPII machinery, which facilitates ER membrane budding to form tubular-vesicular ER whorl precursors. ER whorl precursors then go through Sec22b-mediated fusion to form ER whorls. We further show that ER whorls contribute to ER stress-induced translational inhibition by possibly modulating PERK activity and by sequestering translocons in a ribosome-free environment. We propose that formation of ER whorls reflects a new type of ER stress response that controls inhibition of protein translation.
    DOI:  https://doi.org/10.1038/s41422-020-00416-2
  9. JCI Insight. 2020 Oct 02. pii: 136078. [Epub ahead of print]5(19):
    Nna1 gene deficiency triggers Purkinje neuron death by tubulin hyperglutamylation and ER dysfunction.
    Jianxue Li, Evan Y Snyder, Fenny Hf Tang, Renata Pasqualini, Wadih Arap, Richard L Sidman.
      Posttranslational glutamylation/deglutamylation balance in tubulins influences dendritic maturation and neuronal survival of cerebellar Purkinje neurons (PNs). PNs and some additional neuronal types degenerate in several spontaneous, independently occurring Purkinje cell degeneration (pcd) mice featuring mutant neuronal nuclear protein induced by axotomy (Nna1), a deglutamylase gene. This defective deglutamylase allows glutamylases to form hyperglutamylated tubulins. In pcd, all PNs die during postnatal "adolescence." Neurons in some additional brain regions also die, mostly later than PNs. We show in laser capture microdissected single PNs, in cerebellar granule cell neuronal clusters, and in dissected hippocampus and substantia nigra that deglutamase mRNA and protein were virtually absent before pcd PNs degenerated, whereas glutaminase mRNA and protein remained normal. Hyperglutamylated microtubules and dimeric tubulins accumulated in pcd PNs and were involved in pcd PN death by glutamylase/deglutamylase imbalance. Importantly, treatment with a microtubule depolymerizer corrected the glutamylation/deglutamylation ratio, increasing PN survival. Further, before onset of neuronal death, pcd PNs displayed prominent basal polylisosomal masses rich in ER. We propose a "seesaw" metamorphic model summarizing mutant Nna1-induced tubulin hyperglutamylation, the pcd's PN phenotype, and report that the neuronal disorder involved ER stress, unfolded protein response, and protein synthesis inhibition preceding PN death by apoptosis/necroptosis.
    Keywords:  Neurodegeneration; Neuroscience
    DOI:  https://doi.org/10.1172/jci.insight.136078
  10. Int J Mol Sci. 2020 Sep 26. pii: E7097. [Epub ahead of print]21(19):
    Prolonged Lipid Accumulation in Cultured Primary Human Hepatocytes Rather Leads to ER Stress than Oxidative Stress.
    Christiane Rennert, Theresa Heil, Gerda Schicht, Anna Stilkerich, Lena Seidemann, Victoria Kegel-Hübner, Daniel Seehofer, Georg Damm.
      Overweight has become a major health care problem in Western societies and is accompanied by an increasing incidence and prevalence of non-alcoholic fatty liver disease (NAFLD). The progression from NAFLD to non-alcoholic steatohepatitis (NASH) marks a crucial tipping point in the progression of severe and irreversible liver diseases. This study aims to gain further insight into the molecular processes leading to the evolution from steatosis to steatohepatitis. Steatosis was induced in cultures of primary human hepatocytes by continuous five-day exposure to free fatty acids (FFAs). The kinetics of lipid accumulation, lipotoxicity, and oxidative stress were measured. Additionally, ER stress was evaluated by analyzing the protein expression profiles of its key players: PERK, IRE1a, and ATF6a. Our data revealed that hepatocytes are capable of storing enormous amounts of lipids without showing signs of lipotoxicity. Prolonged lipid accumulation did not create an imbalance in hepatocyte redox homeostasis or a reduction in antioxidative capacity. However, we observed an FFA-dependent increase in ER stress, revealing thresholds for triggering the activation of pathways associated with lipid stress, inhibition of protein translation, and apoptosis. Our study clearly showed that even severe lipid accumulation can be attenuated by cellular defenses, but regenerative capacities may be reduced.
    Keywords:  ER stress; NAFLD; NASH; liver; oxidative stress; primary human hepatocytes; steatosis
    DOI:  https://doi.org/10.3390/ijms21197097
  11. Immunol Lett. 2020 Sep 28. pii: S0165-2478(20)30385-0. [Epub ahead of print]
    Regulation of Cellular Immunity by Activating Transcription Factor 4.
    Debasmita Mukherjee, Lena S Bercz, Molly A Torok, Thomas A Mace.
      Activating transcription factor 4 (ATF4) is a DNA binding transcription factor belonging to the family of basic Leucine zipper proteins. ATF4 can be activated in response to multiple cellular stress signals including endoplasmic reticulum stress in the event of improper protein folding or oxidative stress because of mitochondrial dysfunction as well as hypoxia. There are multiple downstream targets of ATF4 that can coordinate the regulation between survival and apoptosis of a cell based on time and exposure to stress. ATF4, therefore, has a broad range of control that results in the modulation of immune cells of the innate and adaptive responses leading to regulation of the cellular immunity. Studies provide evidence that ATF4 can regulate immune cells such as macrophages, T cells, B cells, NK cells and dendritic cells contributing to progression of disease. Immune cells can be exposed to stressed environment in the event of a pathogen attack, infection, inflammation, or in the tumor microenvironment leading to increased ATF4 activity to regulate these responses. ATF4 can further control differentiation and maturation of different immune cell types becoming a determinant of effective immune regulation. Additionally, ATF4 has been heavily implicated in rendering effector immune cells dysfunctional that are used to target tumorigenesis. Therefore, there is a need to evaluate where the literature stands in understanding the overall role of ATF4 in regulating cellular immunity to identify therapeutic targets and generalized mechanisms for different disease progressions.
    Keywords:  ATF4; Cellular Immunity; ER stress; Unfolded protein response
    DOI:  https://doi.org/10.1016/j.imlet.2020.09.006
  12. PLoS Pathog. 2020 Sep 30. 16(9): e1008918
    A pathogen branched-chain amino acid catabolic pathway subverts host survival by impairing energy metabolism and the mitochondrial UPR.
    Siraje Arif Mahmud, Mohammed Adnan Qureshi, Madhab Sapkota, Mark W Pellegrino.
      The mitochondrial unfolded protein response (UPRmt) is a stress-activated pathway promoting mitochondrial recovery and defense against infection. In C. elegans, the UPRmt is activated during infection with the pathogen Pseudomonas aeruginosa-but only transiently. As this may reflect a pathogenic strategy to target a pathway required for host survival, we conducted a P. aeruginosa genetic screen to uncover mechanisms associated with this temporary activation. Here, we find that loss of the P. aeruginosa acyl-CoA dehydrogenase FadE2 prolongs UPRmt activity and extends host survival. FadE2 shows substrate preferences for the coenzyme A intermediates produced during the breakdown of the branched-chain amino acids valine and leucine. Our data suggests that during infection, FadE2 restricts the supply of these catabolites to the host hindering host energy metabolism in addition to the UPRmt. Thus, a metabolic pathway in P. aeruginosa contributes to pathogenesis during infection through manipulation of host energy status and mitochondrial stress signaling potential.
    DOI:  https://doi.org/10.1371/journal.ppat.1008918
  13. Cells. 2020 Sep 28. pii: E2183. [Epub ahead of print]9(10):
    Proteostasis Disturbances and Inflammation in Neurodegenerative Diseases.
    Tuuli-Maria Sonninen, Gundars Goldsteins, Nihay Laham-Karam, Jari Koistinaho, Šárka Lehtonen.
      Protein homeostasis (proteostasis) disturbances and inflammation are evident in normal aging and some age-related neurodegenerative diseases. While the proteostasis network maintains the integrity of intracellular and extracellular functional proteins, inflammation is a biological response to harmful stimuli. Cellular stress conditions can cause protein damage, thus exacerbating protein misfolding and leading to an eventual overload of the degradation system. The regulation of proteostasis network is particularly important in postmitotic neurons due to their limited regenerative capacity. Therefore, maintaining balanced protein synthesis, handling unfolding, refolding, and degrading misfolded proteins are essential to preserve all cellular functions in the central nervous sysytem. Failing proteostasis may trigger inflammatory responses in glial cells, and the consequent release of inflammatory mediators may lead to disturbances in proteostasis. Here, we review the mechanisms of proteostasis and inflammatory response, emphasizing their role in the pathological hallmarks of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Furthermore, we discuss the interplay between proteostatic stress and excessive immune response that activates inflammation and leads to dysfunctional proteostasis.
    Keywords:  ER stress; ROS; advanced glycation end-products; immunoproteosome; lipid peroxidation; neuroinflammation; pro-inflammatory cytokines; protein misfolding
    DOI:  https://doi.org/10.3390/cells9102183
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