bims-unfpre Biomed News
on Unfolded protein response
Issue of 2023–06–18
eleven papers selected by
Susan Logue, University of Manitoba
  1. PERK signaling promotes mitochondrial elongation by remodeling membrane phosphatidic acid.
  2. Ubiquitin-like protein 5 is a novel player in the UPR-PERK arm and ER stress-induced cell death.
  3. SMURF1 attenuates endoplasmic reticulum stress by promoting the degradation of KEAP1 to activate NRF2 antioxidant pathway.
  4. TMX4-driven LINC complex disassembly and asymmetric autophagy of the nuclear envelope upon acute ER stress.
  5. The unfolded protein response components IRE1α and XBP1 promote human coronavirus infection.
  6. Targeting the ATF6-mediated ER stress response and autophagy blocks integrin-driven prostate cancer progression.
  7. The abrogation of GRP78 sensitizes liver cancer cells to lysionotin by enhancing ER stress-mediated pro-apoptotic pathway.
  8. IRE1α: from the function to the potential therapeutic target in atherosclerosis.
  9. Reducing oxidative protein folding alleviates senescence by minimizing ER-to-nucleus H2 O2 release.
  10. ORP5 promotes migration and invasion of cervical cancer cells by inhibiting endoplasmic reticulum stress.
  11. Endoplasmic reticulum stress-related gene model predicts prognosis and guides therapies in lung adenocarcinoma.
  1. EMBO J. 2023 Jun 12. e113908
    PERK signaling promotes mitochondrial elongation by remodeling membrane phosphatidic acid.
    Valerie Perea, Christian Cole, Justine Lebeau, Vivian Dolina, Kelsey R Baron, Aparajita Madhavan, Jeffery W Kelly, Danielle A Grotjahn, R Luke Wiseman.
      Endoplasmic reticulum (ER) stress and mitochondrial dysfunction are linked in the onset and pathogenesis of numerous diseases. This has led to considerable interest in defining the mechanisms responsible for regulating mitochondria during ER stress. The PERK signaling arm of the unfolded protein response (UPR) has emerged as a prominent ER stress-responsive signaling pathway that regulates diverse aspects of mitochondrial biology. Here, we show that PERK activity promotes adaptive remodeling of mitochondrial membrane phosphatidic acid (PA) to induce protective mitochondrial elongation during acute ER stress. We find that PERK activity is required for ER stress-dependent increases in both cellular PA and YME1L-dependent degradation of the intramitochondrial PA transporter PRELID1. These two processes lead to the accumulation of PA on the outer mitochondrial membrane where it can induce mitochondrial elongation by inhibiting mitochondrial fission. Our results establish a new role for PERK in the adaptive remodeling of mitochondrial phospholipids and demonstrate that PERK-dependent PA regulation adapts organellar shape in response to ER stress.
    Keywords:  endoplasmic reticulum (ER) stress; mitochondrial morphology; phosphatidic acid; unfolded protein response (UPR)
    DOI:  https://doi.org/10.15252/embj.2023113908
  2. J Biol Chem. 2023 Jun 12. pii: S0021-9258(23)01943-9. [Epub ahead of print] 104915
    Ubiquitin-like protein 5 is a novel player in the UPR-PERK arm and ER stress-induced cell death.
    Wei Wang, Adam M Hawkridge, Yibao Ma, Bei Zhang, John B Mangrum, Zaneera H Hassan, Tianhai He, Sofiya Blat, Chunqing Guo, Huiping Zhou, Jinze Liu, Xiang-Yang Wang, Xianjun Fang.
      Biological functions of the highly conserved ubiquitin-like protein 5 (UBL5) are not well understood. In C. elegans, UBL5 is induced under mitochondrial stress to mount the mitochondrial unfolded protein response (UPRmt). However, the role of UBL5 in the more prevalent endoplasmic reticulum (ER) stress-unfolded protein response (UPR) in the mammalian system is unknown. In the present work, we demonstrated that UBL5 was an ER stress-responsive protein, undergoing rapid depletion in mammalian cells and livers of mice. The ER stress-induced UBL5 depletion was mediated by proteasome-dependent yet ubiquitin-independent proteolysis. Activation of the protein kinase R-like endoplasmic reticulum kinase (PERK) arm of the UPR was essential and sufficient for inducing UBL5 degradation. RNA-Seq analysis of UBL5-regulated transcriptome revealed that multiple death pathways were activated in UBL5-silenced cells. In agreement with this, UBL5 knockdown induced severe apoptosis in culture and suppressed tumorigenicity of cancer cells in vivo. Furthermore, overexpression of UBL5 protected specifically against ER stress-induced apoptosis. These results identify UBL5 as a physiologically relevant survival regulator that is proteolytically depleted by the UPR-PERK pathway, linking ER stress to cell death.
    Keywords:  ER stress; PERK; UBL5; UPR; apoptosis; cell survival; proteasome degradation; ubiquitin-independent proteasome system
    DOI:  https://doi.org/10.1016/j.jbc.2023.104915
  3. Cell Death Dis. 2023 Jun 14. 14(6): 361
    SMURF1 attenuates endoplasmic reticulum stress by promoting the degradation of KEAP1 to activate NRF2 antioxidant pathway.
    Lei Dong, Mengchuan Xu, Yang Li, Wanting Xu, Chengwei Wu, Hanfei Zheng, Zhenyu Xiao, Guochen Sun, Lei Ding, Xiaobo Li, Wenming Li, Liying Zhou, Qin Xia.
      Cancer cells consistently utilize the unfolded protein response (UPR) to encounter the abnormal endoplasmic reticulum (ER) stress induced by the accumulation of misfolded proteins. Extreme activation of the UPR could also provoke maladaptive cell death. Previous reports have shown that NRF2 antioxidant signaling is activated by UPR and serves as noncanonical pathway to defense and reduce excessive ROS levels during ER stress. However, the mechanisms of regulating NRF2 signaling upon ER stress in glioblastoma have not been fully elucidated. Here we identify that SMURF1 protects against ER stress and facilitates glioblastoma cell survival by rewiring KEAP1-NRF2 pathway. We show that ER stress induces SMURF1 degradation. Knockdown of SMURF1 upregulates IRE1 and PERK signaling in the UPR pathway and prevents ER-associated protein degradation (ERAD) activity, leading to cell apoptosis. Importantly, SMURF1 overexpression activates NRF2 signaling to reduce ROS levels and alleviate UPR-mediated cell death. Mechanistically, SMURF1 interacts with and ubiquitinates KEAP1 for its degradation (NRF2 negative regulator), resulting in NRF2 nuclear import. Moreover, SMURF1 loss reduces glioblastoma cell proliferation and growth in subcutaneously implanted nude mice xenografts. Taken together, SMURF1 rewires KEAP1-NRF2 pathway to confer resistance to ER stress inducers and protect glioblastoma cell survival. ER stress and SMURF1 modulation may provide promising therapeutic targets for the treatment of glioblastoma.
    DOI:  https://doi.org/10.1038/s41419-023-05873-2
  4. Nat Commun. 2023 Jun 13. 14(1): 3497
    TMX4-driven LINC complex disassembly and asymmetric autophagy of the nuclear envelope upon acute ER stress.
    Marika K Kucińska, Juliette Fedry, Carmela Galli, Diego Morone, Andrea Raimondi, Tatiana Soldà, Friedrich Förster, Maurizio Molinari.
      The endoplasmic reticulum (ER) is an organelle of nucleated cells that produces proteins, lipids and oligosaccharides. ER volume and activity are increased upon induction of unfolded protein responses (UPR) and are reduced upon activation of ER-phagy programs. A specialized domain of the ER, the nuclear envelope (NE), protects the cell genome with two juxtaposed lipid bilayers, the inner and outer nuclear membranes (INM and ONM) separated by the perinuclear space (PNS). Here we report that expansion of the mammalian ER upon homeostatic perturbations results in TMX4 reductase-driven disassembly of the LINC complexes connecting INM and ONM and in ONM swelling. The physiologic distance between ONM and INM is restored, upon resolution of the ER stress, by asymmetric autophagy of the NE, which involves the LC3 lipidation machinery, the autophagy receptor SEC62 and the direct capture of ONM-derived vesicles by degradative LAMP1/RAB7-positive endolysosomes in a catabolic pathway mechanistically defined as micro-ONM-phagy.
    DOI:  https://doi.org/10.1038/s41467-023-39172-3
  5. mBio. 2023 Jun 12. e0054023
    The unfolded protein response components IRE1α and XBP1 promote human coronavirus infection.
    Jessica M Oda, Andreas B den Hartigh, Shoen M Jackson, Ana R Tronco, Susan L Fink.
      The cellular processes that support human coronavirus replication and contribute to the pathogenesis of severe disease remain incompletely understood. Many viruses, including coronaviruses, cause endoplasmic reticulum (ER) stress during infection. IRE1α is a component of the cellular response to ER stress that initiates non-conventional splicing of XBP1 mRNA. Spliced XBP1 encodes a transcription factor that induces the expression of ER-related targets. Activation of the IRE1α-XBP1 pathway occurs in association with risk factors for severe human coronavirus infection. In this study, we found that the human coronaviruses HCoV-OC43 (human coronavirus OC43) and SARS-CoV-2 (severe acute respiratory syndrome coronavirus-2) both robustly activate the IRE1α-XBP1 branch of the unfolded protein response in cultured cells. Using IRE1α nuclease inhibitors and genetic knockdown of IRE1α and XBP1, we found that these host factors are required for optimal replication of both viruses. Our data suggest that IRE1α supports infection downstream of initial viral attachment and entry. In addition, we found that ER stress-inducing conditions are sufficient to enhance human coronavirus replication. Furthermore, we found markedly increased XBP1 in circulation in human patients with severe coronavirus disease 2019 (COVID-19). Together, these results demonstrate the importance of IRE1α and XBP1 for human coronavirus infection.IMPORTANCEThere is a critical need to understand the cellular processes co-opted during human coronavirus replication, with an emphasis on identifying mechanisms underlying severe disease and potential therapeutic targets. Here, we demonstrate that the host proteins IRE1α and XBP1 are required for robust infection by the human coronaviruses, SARS-CoV-2 and HCoV-OC43. IRE1α and XBP1 participate in the cellular response to ER stress and are activated during conditions that predispose to severe COVID-19. We found enhanced viral replication with exogenous IRE1α activation, and evidence that this pathway is activated in humans during severe COVID-19. Together, these results demonstrate the importance of IRE1α and XBP1 for human coronavirus infection.
    Keywords:  ER stress; HCoV-OC43; IRE1α; SARS-CoV-2; XBP1; coronavirus; endoplasmic reticulum; unfolded protein response
    DOI:  https://doi.org/10.1128/mbio.00540-23
  6. Mol Cancer Res. 2023 Jun 14. pii: MCR-23-0108. [Epub ahead of print]
    Targeting the ATF6-mediated ER stress response and autophagy blocks integrin-driven prostate cancer progression.
    Amanda J Macke, Artem N Pachikov, Taylor E Divita, Mary E Morris, Chad A LaGrange, Melissa S Holzapfel, Anatoly V Kubyshkin, Evgeniya Y Zyablitskaya, Tatiana P Makalish, Sergey N Eremenko, Haowen Qiu, Jean-Jack M Riethoven, George P Hemstreet, Armen Petrosyan.
      Prostate cancer (PCa) progression to the lethal metastatic castration-resistant phenotype (mCRPC) is driven by αv integrins and is associated with Golgi disorganization and activation of the ATF6 branch of unfolded protein response (UPR). Overexpression of integrins requires N-acetylglucosaminyltransferase-V (MGAT5)-mediated glycosylation and subsequent cluster formation with Galectin-3 (Gal-3). However, the mechanism underlying this altered glycosylation is missing. For the first time, using HALO analysis of immunohistochemistry, we found a strong association of Integrin αv and Gal-3 at the plasma membrane (PM) in primary PCa and mCRPC samples. We discovered that MGAT5 activation is caused by Golgi fragmentation and mislocalization of its competitor, N-acetylglucosaminyltransferase-III, MGAT3, from Golgi to the endoplasmic reticulum (ER). This was validated in an ethanol-induced model of ER stress, where alcohol treatment in androgen-refractory PC-3 and DU145 cells or alcohol consumption in PCa patient samples aggravates Golgi scattering, activates MGAT5, and enhances integrin expression at PM. This explains known link between alcohol consumption and PCa mortality. ATF6 depletion significantly blocks UPR and reduces the number of Golgi fragments in both PC-3 and DU145 cells. Inhibition of autophagy by hydroxychloroquine (HCQ) restores compact Golgi, rescues MGAT3 intra-Golgi localization, blocks glycan modification via MGAT5, and abrogates delivery of Gal-3 to the cell surface. Importantly, the loss of Gal-3 leads to reduced integrins at PM and their accelerated internalization. ATF6 depletion and HCQ treatment synergistically decrease Integrin αv and Gal-3 expression and temper orthotopic tumor growth and metastasis. Implications: Combined ablation of ATF6 and autophagy can serve as new mCRPC therapeutic.
    DOI:  https://doi.org/10.1158/1541-7786.MCR-23-0108
  7. Cell Stress Chaperones. 2023 Jun 16.
    The abrogation of GRP78 sensitizes liver cancer cells to lysionotin by enhancing ER stress-mediated pro-apoptotic pathway.
    Ying Zou, Hewen Shi, Haiyan Lin, Xiaoxue Wang, Guoli Wang, Yijia Gao, Fan Yi, Yancun Yin, Defang Li, Minjing Li.
      Glucose-regulated protein 78 (GRP78) is frequently and highly expressed in various human malignancies and protects cancer cells against apoptosis induced by multifarious stresses, particularly endoplasmic reticulum stress (ER stress). The inhibition of GRP78 expression or activity could enhance apoptosis induced by anti-tumor drugs or compounds. Herein, we will evaluate the efficacy of lysionotin in the treatment of human liver cancer as well as the molecular mechanism. Moreover, we will examine whether inhibition of GRP78 enhanced the sensitivity of hepatocellular carcinoma cells to lysionotin. We found that lysionotin significantly suppressed proliferation and induced apoptosis of liver cancer cells. TEM showed that lysionotin-treated liver cancer cells showed an extensively distended and dilated endoplasmic reticulum lumen. Meanwhile, the levels of the ER stress hallmark GRP78 and UPR hallmarks (e.g., IRE1α and CHOP) were significantly increased in response to lysionotin treatment in liver cancer cells. Moreover, the reactive oxygen species (ROS) scavenger NAC and caspase-3 inhibitor Ac-DEVD-CHO visibly attenuated the induction of GRP78 and attenuated the decrease in cell viability induced by lysionotin. More importantly, the knockdown of GRP78 expression by siRNAs or treatment with EGCG, both induced remarkable increase in lysionotin-induced PARP and pro-caspase-3 cleavage and JNK phosphorylation. In addition, knockdown of GRP78 expression by siRNA or suppression GRP78 activity by EGCG both significantly improved the effectiveness of lysionotin. These data indicated that pro-survival GRP78 induction may contribute to lysionotin resistance. The combination of EGCG and lysionotin is suggested to represent a novel approach in cancer chemo-prevention and therapeutics.
    Keywords:  Apoptosis; Endoplasmic reticulum stress; Glucose-regulated protein 78; Liver cancer; Lysionotin; Unfolded protein response
    DOI:  https://doi.org/10.1007/s12192-023-01358-5
  8. Mol Cell Biochem. 2023 Jun 13.
    IRE1α: from the function to the potential therapeutic target in atherosclerosis.
    Zheng-Yang Zhou, Li Wu, Yi-Fan Liu, Mu-Yao Tang, Jing-Yi Tang, Ya-Qian Deng, Lei Liu, Bin-Bin Nie, Zi-Kai Zou, Liang Huang.
      Inositol requiring enzyme 1 (IRE1) is generally thought to control the most conserved pathway in the unfolded protein response (UPR). Two isoforms of IRE1, IRE1α and IRE1β, have been reported in mammals. IRE1α is a ubiquitously expressed protein whose knockout shows marked lethality. In contrast, the expression of IRE1β is exclusively restricted in the epithelial cells of the respiratory and gastrointestinal tracts, and IRE1β-knockout mice are phenotypically normal. As research continues to deepen, IRE1α was showed to be tightly linked to inflammation, lipid metabolism regulation, cell death and so on. Growing evidence also suggests an important role for IRE1α in promoting atherosclerosis (AS) progression and acute cardiovascular events through disrupting lipid metabolism balance, facilitating cells apoptosis, accelerating inflammatory responses and promoting foam cell formation. In addition, IRE1α was recognized as novel potential therapeutic target in AS prevention. This review provides some clues about the relationship between IRE1α and AS, hoping to contribute to further understanding roles of IRE1α in atherogenesis and to be helpful for the design of novel efficacious therapeutics agents targeting IRE1α-related pathways.
    Keywords:  Atherosclerosis; Endoplasmic reticulum stress; IRE1α; X-box binding protein 1
    DOI:  https://doi.org/10.1007/s11010-023-04780-6
  9. EMBO Rep. 2023 Jun 12. e56439
    Reducing oxidative protein folding alleviates senescence by minimizing ER-to-nucleus H2 O2 release.
    Fang Cheng, Qianzhao Ji, Lu Wang, Chih-Chen Wang, Guang-Hui Liu, Lei Wang.
      Oxidative protein folding occurs in the endoplasmic reticulum (ER) to generate disulfide bonds, and the by-product is hydrogen peroxide (H2 O2 ). However, the relationship between oxidative protein folding and senescence remains uncharacterized. Here, we find that the protein disulfide isomerase (PDI), a key oxidoreductase that catalyzes oxidative protein folding, accumulated in aged human mesenchymal stem cells (hMSCs) and deletion of PDI alleviated hMSCs senescence. Mechanistically, knocking out PDI slows the rate of oxidative protein folding and decreases the leakage of ER-derived H2 O2 into the nucleus, thereby decreasing the expression of SERPINE1, which was identified as a key driver of cell senescence. Furthermore, we show that depletion of PDI alleviated senescence in various cell models of aging. Our findings reveal a previously unrecognized role of oxidative protein folding in promoting cell aging, providing a potential target for aging and aging-related disease intervention.
    Keywords:  human mesenchymal stem cells (hMSCs); hydrogen peroxide (H2O2); oxidative protein folding; protein disulfide isomerase (PDI); senescence
    DOI:  https://doi.org/10.15252/embr.202256439
  10. Cell Stress Chaperones. 2023 Jun 14.
    ORP5 promotes migration and invasion of cervical cancer cells by inhibiting endoplasmic reticulum stress.
    Yi Wu, Luyao Min, Peng Zhang, Lin Zhang, Yuting Xu, Danhua Li, Maojin Zheng, Dongsheng Pei, Qingling Wang.
      ORP5 is a transmembrane protein anchored to the endoplasmic reticulum, which mainly functions as a lipid transporter and has reportedly been linked to cancer. However, the specific mechanism of ORP5 action in cervical cancer (CC) is unclear. In this study, we found that ORP5 promotes the migration and invasive ability of CC cells in vitro and in vivo. In addition, ORP5 expression was linked to endoplasmic reticulum stress, and ORP5 encouraged CC metastasis by inhibiting endoplasmic reticulum stress. Mechanistically, ORP5 inhibited endoplasmic reticulum stress in CC cells by stimulating ubiquitination and proteasomal degradation of SREBP1 to reduce its expression. In conclusion, ORP5 promotes the malignant progression of CC by inhibiting endoplasmic reticulum stress, providing a therapeutic target and strategy for CC treatment.
    Keywords:  Cervical cancer; Endoplasmic reticulum stress; ORP5; SREBP1; Ubiquitination
    DOI:  https://doi.org/10.1007/s12192-023-01357-6
  11. BMC Bioinformatics. 2023 Jun 16. 24(1): 255
    Endoplasmic reticulum stress-related gene model predicts prognosis and guides therapies in lung adenocarcinoma.
    Yuqi Song, Jianzun Ma, Linan Fang, Mingbo Tang, Xinliang Gao, Dongshan Zhu, Wei Liu.
       BACKGROUND: The prognosis and survival of lung adenocarcinoma (LUAD) patients are still not promising despite recent breakthroughs in treatment. Endoplasmic reticulum stress (ERS) is a self-protective mechanism resulting from an imbalance in quality control of unfolded proteins when cells are stressed, which plays an active role in lung cancer development, but the relationship between ERS and the pathological characteristics and clinical prognosis of LUAD patients remains unclear.
    METHODS: LASSO and Cox regression were applied based on sequencing information to construct the model, which was validated to be robust. The risk scores of the patients were calculated using the formula provided by the model, and the patients were divided into high and low-risk groups according to the median cut-off of risk scores. Cox regression analysis identifies independent prognostic factors for these patients, and enrichment analysis of prognosis-related genes was also performed. The relationship between risk scores and tumor mutation burden (TMB), cancer stem cell index, and drug sensitivity was explored.
    RESULTS: We constructed a 13-gene prognostic model for LUAD patients. Patients in the high-risk group had worse overall survival, lower immune score and ESTIMATE score, higher TMB, higher cancer stem cell index, and higher sensitivity to conventional chemotherapeutic agents. In addition, we constructed a nomogram that predicts 5-year survival in LUAD patients, which helps clinicians to foresee the prognosis from a new perspective.
    CONCLUSIONS: Our results highlight the association of ERS with LUAD and the potential use of ERS in guiding treatment.
    Keywords:  Endoplasmic Reticulum Stress; Gene Model; Lung Adenocarcinoma; Prognosis; Therapy
    DOI:  https://doi.org/10.1186/s12859-023-05384-z
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