bims-unfpre Biomed News
on Unfolded protein response
Issue of 2021–07–25
twelve papers selected by
Susan Logue, University of Manitoba
  1. A small-molecule activator of the unfolded protein response eradicates human breast tumors in mice.
  2. IRE1α regulates skeletal muscle regeneration through Myostatin mRNA decay.
  3. IRE1 signaling regulates chondrocyte apoptosis and death fate in the osteoarthritis.
  4. SIMP1 modulates salt tolerance by elevating ERAD efficiency through UMP1A-mediated proteasome maturation in plants.
  5. Endoplasmic reticulum stress‑induced cell death as a potential mechanism for targeted therapy in glioblastoma (Review).
  6. Current Status of Endoplasmic Reticulum Stress in Type II Diabetes.
  7. GRP78 determines glioblastoma sensitivity to UBA1 inhibition-induced UPR signaling and cell death.
  8. Oncolytic Virus-Induced Autophagy in Glioblastoma.
  9. Untargeted metabolomics and transcriptomics identified glutathione metabolism disturbance and PCS and TMAO as potential biomarkers for ER stress in lung.
  10. The regulation of ferroptosis by MESH1 through the activation of the integrative stress response.
  11. Loss of PIKfyve drives the spongiform degeneration in prion diseases.
  12. Insulin-induced genes INSIG1 and INSIG2 mediate oxysterol-dependent activation of the PERK/eIF2α/ATF4 axis.
  1. Sci Transl Med. 2021 Jul 21. pii: eabf1383. [Epub ahead of print]13(603):
    A small-molecule activator of the unfolded protein response eradicates human breast tumors in mice.
    Matthew W Boudreau, Darjan Duraki, Lawrence Wang, Chengjian Mao, Ji Eun Kim, Madeline A Henn, Bingtao Tang, Sean W Fanning, Jeffrey Kiefer, Theodore M Tarasow, Elizabeth M Bruckheimer, Ramon Moreno, Spyro Mousses, Geoffrey L Greene, Edward J Roy, Ben Ho Park, Timothy M Fan, Erik R Nelson, Paul J Hergenrother, David J Shapiro.
      Metastatic estrogen receptor α (ERα)-positive breast cancer is presently incurable. Seeking to target these drug-resistant cancers, we report the discovery of a compound, called ErSO, that activates the anticipatory unfolded protein response (a-UPR) and induces rapid and selective necrosis of ERα-positive breast cancer cell lines in vitro. We then tested ErSO in vivo in several preclinical orthotopic and metastasis mouse models carrying different xenografts of human breast cancer lines or patient-derived breast tumors. In multiple orthotopic models, ErSO treatment given either orally or intraperitoneally for 14 to 21 days induced tumor regression without recurrence. In a cell line tail vein metastasis model, ErSO was also effective at inducing regression of most lung, bone, and liver metastases. ErSO treatment induced almost complete regression of brain metastases in mice carrying intracranial human breast cancer cell line xenografts. Tumors that did not undergo complete regression and regrew remained sensitive to retreatment with ErSO. ErSO was well tolerated in mice, rats, and dogs at doses above those needed for therapeutic responses and had little or no effect on normal ERα-expressing murine tissues. ErSO mediated its anticancer effects through activation of the a-UPR, suggesting that activation of a tumor protective pathway could induce tumor regression.
    DOI:  https://doi.org/10.1126/scitranslmed.abf1383
  2. J Clin Invest. 2021 Jul 20. pii: 143737. [Epub ahead of print]
    IRE1α regulates skeletal muscle regeneration through Myostatin mRNA decay.
    Shengqi He, Tingting Fu, Yue Yu, Qinhao Liang, Luyao Li, Jing Liu, Xuan Zhang, Qian Zhou, Qiqi Guo, Dengqiu Xu, Yong Chen, Xiaolong Wang, Yulin Chen, Jianmiao Liu, Zhenji Gan, Yong Liu.
      Skeletal muscle can undergo a regenerative process from injury or disease to preserve muscle mass and function, which is critically influenced by cellular stress responses. Inositol-requiring enzyme 1 (IRE1) is an ancient endoplasmic reticulum (ER) stress sensor and mediates a key branch of the unfolded protein response (UPR). In mammals, IRE1α is implicated in the homeostatic control of stress responses during tissue injury and regeneration. Here, we show that IRE1α serves as a myogenic regulator in skeletal muscle regeneration in response to injury and muscular dystrophy. We found in mice that IRE1α was activated during injury-induced muscle regeneration, and muscle-specific IRE1α ablation resulted in impaired regeneration upon cardiotoxin-induced injury. Gain- and loss-of-function studies in myocytes demonstrated that IRE1αacts to sustain both differentiation in myoblasts and hypertrophy in myotubes through regulated IRE1-dependent decay (RIDD) of mRNA encoding Myostatin, a key negative regulator of muscle repair and growth. Furthermore, in the mouse model of Duchenne muscular dystrophy (DMD), loss of muscle IRE1α resulted in augmented Myostatin signaling and exacerbated the dystrophic phenotypes. Thus, these results reveal a pivotal role for the RIDD output of IRE1α in muscle regeneration, offering new insight into potential therapeutic strategies for muscle loss diseases.
    Keywords:  Cell stress; Molecular pathology; Muscle Biology; Skeletal muscle
    DOI:  https://doi.org/10.1172/JCI143737
  3. J Cell Physiol. 2021 Jul 23.
    IRE1 signaling regulates chondrocyte apoptosis and death fate in the osteoarthritis.
    Rongxiang Huang, Zhang Hui, Sun Wei, Duan Li, Wencui Li, Wang Daping, Murad Alahdal.
      IRE1 is an important central regulator of unfolded protein response (UPR) in the endoplasmic reticulum (ER) because of its ability to regulate cell fate as a function of stress sensing. When misfolded proteins accumulated in chondrocytes ER, IRE1 disintegrates with BIP/GRP78 and undergoes dimer/oligomerization and transautophosphorylation. These two processes are mediated through an enzyme activity of IRE1 to activate endoribonuclease and generates XBP1 by unconventional splicing of XBP1 messenger RNA. Thereby promoting the transcription of UPR target genes and apoptosis. The deficiency of inositol-requiring enzyme 1α (IRE1α) in chondrocytes downregulates prosurvival factors XBP1S and Bcl-2, which enhances the apoptosis of chondrocytes through increasing proapoptotic factors caspase-3, p-JNK, and CHOP. Meanwhile, the activation of IRE1α increases chondrocyte viability and reduces cell apoptosis. However, the understanding of IRE1 responses and cell death fate remains controversial. This review provides updated data about the role IRE1 plays in chondrocytes and new insights about the potential efficacy of IRE1 regulation in cartilage repair and osteoarthritis treatment.
    Keywords:  ERS; IRE1; apoptosis; chondrocyte; osteoarthritis
    DOI:  https://doi.org/10.1002/jcp.30537
  4. New Phytol. 2021 Jul 17.
    SIMP1 modulates salt tolerance by elevating ERAD efficiency through UMP1A-mediated proteasome maturation in plants.
    Jiaxian He, Yufen Zhuang, Chuan Li, Xia Sun, Shuangshuang Zhao, Changle Ma, Honghui Lin, Huapeng Zhou.
      Salt stress significantly induces accumulation of misfolded or unfolded proteins in plants. Endoplasmic reticulum (ER)-associated protein degradation (ERAD) and other degradative machineries function in the degradation of these abnormal proteins, leading to enhanced salt tolerance in plants. Here we characterize that a novel receptor-like kinase, Salt Induced Malectin-like domain-containing Protein1 (SIMP1), elevates ERAD efficiency during salt stress through UMP1A, a putative proteasome maturation factor in Arabidopsis. SIMP1 loss-of-function caused a salt-hypersensitive phenotype. SIMP1 interacts and phosphorylates UMP1A, and the protein stability of UMP1A is positively regulated by SIMP1. SIMP1 modulates the 26S proteasome maturation possibly through enhancing the recruitment of specific β subunits of the core catalytic particle to UMP1A. Functionally, SIMP1-UMP1A module plays a positive role in ERAD efficiency in Arabidopsis. The degradation of misfolded/unfolded proteins was impaired in both simp1 and ump1a mutants during salt stress. Consistently, both simp1 and ump1a plants exhibited reduced ER stress tolerance. Phenotypic analysis revealed that SIMP1 regulates salt tolerance through UMP1A at least in part. Taken together, our work demonstrated that SIMP1 modulates plant salt tolerance by promoting proteasome maturation via UMP1A, therefore mitigating ER stress through enhanced ERAD efficiency under saline condition.
    Keywords:   Arabidopsis thaliana ; ER stress; ERAD; Plant salt tolerance; UMP1A; proteasome maturation factor
    DOI:  https://doi.org/10.1111/nph.17628
  5. Int J Oncol. 2021 Aug;pii: 60. [Epub ahead of print]59(2):
    Endoplasmic reticulum stress‑induced cell death as a potential mechanism for targeted therapy in glioblastoma (Review).
    Pengfei Shi, Zhuohang Zhang, Jie Xu, Li Zhang, Hongjuan Cui.
      The endoplasmic reticulum (ER) is an essential organelle for protein synthesis, folding and modification, lipid synthesis, and calcium storage. When endogenous or exogenous stimuli lead to ER‑synthesized protein folding dysfunction, numerous unfolded or misfolded proteins accumulate in the ER cavity and cause a series of subsequent responses, referred to as ER stress. If ER stress is continuous, the unfolded protein response (UPR) is not enough to remove the accumulated unfolded and misfolded proteins, and thus, UPR signaling pathways will drive cell apoptosis. Glioblastoma (GBM) is currently the most aggressive and common malignant tumor of the nervous system. Since ER stress may increase the sensitivity of GBM to temozolomide, this article reviews the possible mechanisms of ER stress‑induced apoptosis and the factors affecting ER stress, and evaluates the potential of ER stress as a therapeutic target.
    Keywords:  apoptosis; compounds; endoplasmic reticulum stress; glioblastoma; unfolded protein response
    DOI:  https://doi.org/10.3892/ijo.2021.5240
  6. Molecules. 2021 Jul 19. pii: 4362. [Epub ahead of print]26(14):
    Current Status of Endoplasmic Reticulum Stress in Type II Diabetes.
    Sagir Mustapha, Mustapha Mohammed, Ahmad Khusairi Azemi, Abubakar Ibrahim Jatau, Aishatu Shehu, Lukman Mustapha, Ibrahim Muazzamu Aliyu, Rabi'u Nuhu Danraka, Abdulbasit Amin, Auwal Adam Bala, Wan Amir Nizam Wan Ahmad, Aida Hanum Ghulam Rasool, Mohd Rais Mustafa, Siti Safiah Mokhtar.
      The endoplasmic reticulum (ER) plays a multifunctional role in lipid biosynthesis, calcium storage, protein folding, and processing. Thus, maintaining ER homeostasis is essential for cellular functions. Several pathophysiological conditions and pharmacological agents are known to disrupt ER homeostasis, thereby, causing ER stress. The cells react to ER stress by initiating an adaptive signaling process called the unfolded protein response (UPR). However, the ER initiates death signaling pathways when ER stress persists. ER stress is linked to several diseases, such as cancer, obesity, and diabetes. Thus, its regulation can provide possible therapeutic targets for these. Current evidence suggests that chronic hyperglycemia and hyperlipidemia linked to type II diabetes disrupt ER homeostasis, thereby, resulting in irreversible UPR activation and cell death. Despite progress in understanding the pathophysiology of the UPR and ER stress, to date, the mechanisms of ER stress in relation to type II diabetes remain unclear. This review provides up-to-date information regarding the UPR, ER stress mechanisms, insulin dysfunction, oxidative stress, and the therapeutic potential of targeting specific ER stress pathways.
    Keywords:  apoptosis; endoplasmic reticulum; endoplasmic reticulum stress; homeostasis; type II diabetes; unfolded protein response
    DOI:  https://doi.org/10.3390/molecules26144362
  7. Cell Death Dis. 2021 Jul 23. 12(8): 733
    GRP78 determines glioblastoma sensitivity to UBA1 inhibition-induced UPR signaling and cell death.
    Guanzheng Liu, Jiefeng Yu, Runqiu Wu, Lin Shi, Xu Zhang, Wanhong Zhang, Xiaomin Zhong, Yifeng Wang, Huan Li, Yang Shen, Changyong Wu, Rutong Yu, Mingshan Niu, Xuejiao Liu.
      Glioblastoma multiforme (GBM) is an extremely aggressive brain tumor for which new therapeutic approaches are urgently required. Unfolded protein response (UPR) plays an important role in the progression of GBM and is a promising target for developing novel therapeutic interventions. We identified ubiquitin-activating enzyme 1 (UBA1) inhibitor TAK-243 that can strongly induce UPR in GBM cells. In this study, we evaluated the functional activity and mechanism of TAK-243 in preclinical models of GBM. TAK-243 significantly inhibited the survival, proliferation, and colony formation of GBM cell lines and primary GBM cells. It also revealed a significant anti-tumor effect on a GBM PDX animal model and prolonged the survival time of tumor-bearing mice. Notably, TAK-243 more effectively inhibited the survival and self-renewal ability of glioblastoma stem cells (GSCs) than GBM cells. Importantly, we found that the expression level of GRP78 is a key factor in determining the sensitivity of differentiated GBM cells or GSCs to TAK-243. Mechanistically, UBA1 inhibition disrupts global protein ubiquitination in GBM cells, thereby inducing ER stress and UPR. UPR activates the PERK/ATF4 and IRE1α/XBP signaling axes. These findings indicate that UBA1 inhibition could be an attractive strategy that may be potentially used in the treatment of patients with GBM, and GRP78 can be used as a molecular marker for personalized treatment by targeting UBA1.
    DOI:  https://doi.org/10.1038/s41419-021-04023-w
  8. Cancers (Basel). 2021 Jul 12. pii: 3482. [Epub ahead of print]13(14):
    Oncolytic Virus-Induced Autophagy in Glioblastoma.
    Margarita Kamynina, Salome Tskhovrebova, Jawad Fares, Peter Timashev, Anastasia Laevskaya, Ilya Ulasov.
      Autophagy is a catabolic process that allows cells to scavenge damaged organelles and produces energy to maintain cellular homeostasis. It is also an effective defense method for cells, which allows them to identify an internalized pathogen and destroy it through the fusion of the autophagosome and lysosomes. Recent reports have demonstrated that various chemotherapeutic agents and viral gene therapeutic vehicles provide therapeutic advantages for patients with glioblastoma as monotherapy or in combination with standards of care. Despite nonstop efforts to develop effective antiglioma therapeutics, tumor-induced autophagy in some studies manifests tumor resistance and glioma progression. Here, we explore the functional link between autophagy regulation mediated by oncolytic viruses and discuss how intracellular interactions control autophagic signaling in glioblastoma. Autophagy induced by oncolytic viruses plays a dual role in cell death and survival. On the one hand, autophagy stimulation has mostly led to an increase in cytotoxicity mediated by the oncolytic virus, but, on the other hand, autophagy is also activated as a cell defense mechanism against intracellular pathogens and modulates antiviral activity through the induction of ER stress and unfolded protein response (UPR) signaling. Despite the fact that the moment of switch between autophagic prosurvival and prodeath modes remains to be known, in the context of oncolytic virotherapy, cytotoxic autophagy is a crucial mechanism of cancer cell death.
    Keywords:  apoptosis; autophagy; oncolytic virus
    DOI:  https://doi.org/10.3390/cancers13143482
  9. Sci Rep. 2021 Jul 19. 11(1): 14680
    Untargeted metabolomics and transcriptomics identified glutathione metabolism disturbance and PCS and TMAO as potential biomarkers for ER stress in lung.
    Zijing Wang, Peng Ma, Yisa Wang, Biyu Hou, Can Zhou, He Tian, Bowen Li, Guanghou Shui, Xiuying Yang, Guifen Qiang, Chengqian Yin, Guanhua Du.
      Endoplasmic reticulum (ER) stress is a cellular state that results from the overload of unfolded/misfolded protein in the ER that, if not resolved properly, can lead to cell death. Both acute lung infections and chronic lung diseases have been found related to ER stress. Yet no study has been presented integrating metabolomic and transcriptomic data from total lung in interpreting the pathogenic state of ER stress. Total mouse lungs were used to perform LC-MS and RNA sequencing in relevance to ER stress. Untargeted metabolomics revealed 16 metabolites of aberrant levels with statistical significance while transcriptomics revealed 1593 genes abnormally expressed. Enrichment results demonstrated the injury ER stress inflicted upon lung through the alteration of multiple critical pathways involving energy expenditure, signal transduction, and redox homeostasis. Ultimately, we have presented p-cresol sulfate (PCS) and trimethylamine N-oxide (TMAO) as two potential ER stress biomarkers. Glutathione metabolism stood out in both omics as a notably altered pathway that believed to take important roles in maintaining the redox homeostasis in the cells critical for the development and relief of ER stress, in consistence with the existing reports.
    DOI:  https://doi.org/10.1038/s41598-021-92779-8
  10. Cell Death Dis. 2021 Jul 22. 12(8): 727
    The regulation of ferroptosis by MESH1 through the activation of the integrative stress response.
    Chao-Chieh Lin, Chien-Kuang Cornelia Ding, Tianai Sun, Jianli Wu, Kai-Yuan Chen, Pei Zhou, Jen-Tsan Chi.
      All organisms exposed to metabolic and environmental stresses have developed various stress adaptive strategies to maintain homeostasis. The main bacterial stress survival mechanism is the stringent response triggered by the accumulation "alarmone" (p)ppGpp, whose level is regulated by RelA and SpoT. While metazoan genomes encode MESH1 (Metazoan SpoT Homolog 1) with ppGpp hydrolase activity, neither ppGpp nor the stringent response is found in metazoa. The deletion of Mesh1 in Drosophila triggers a transcriptional response reminiscent of the bacterial stringent response. However, the function of MESH1 remains unknown until our recent discovery of MESH1 as the first cytosolic NADPH phosphatase that regulates ferroptosis. To further understand whether MESH1 knockdown triggers a similar transcriptional response in mammalian cells, here, we employed RNA-Seq to analyze the transcriptome response to MESH1 knockdown in human cancer cells. We find that MESH1 knockdown induced different genes involving endoplasmic reticulum (ER) stress, especially ATF3, one of the ATF4-regulated genes in the integrative stress responses (ISR). Furthermore, MESH1 knockdown increased ATF4 protein, eIF2a phosphorylation, and induction of ATF3, XBPs, and CHOP mRNA. ATF4 induction contributes to ~30% of the transcriptome induced by MESH1 knockdown. Concurrent ATF4 knockdown re-sensitizes MESH1-depleted RCC4 cells to ferroptosis, suggesting its role in the ferroptosis protection mediated by MESH1 knockdown. ATF3 induction is abolished by the concurrent knockdown of NADK, implicating a role of NADPH accumulation in the integrative stress response. Collectively, these results suggest that MESH1 depletion triggers ER stress and ISR as a part of its overall transcriptome changes to enable stress survival of cancer cells. Therefore, the phenotypic similarity of stress tolerance caused by MESH1 removal and NADPH accumulation is in part achieved by ISR to regulate ferroptosis.
    DOI:  https://doi.org/10.1038/s41419-021-04018-7
  11. EMBO Mol Med. 2021 Jul 22. e14714
    Loss of PIKfyve drives the spongiform degeneration in prion diseases.
    Asvin K K Lakkaraju, Karl Frontzek, Emina Lemes, Uli Herrmann, Marco Losa, Rajlakshmi Marpakwar, Adriano Aguzzi.
      Brain-matter vacuolation is a defining trait of all prion diseases, yet its cause is unknown. Here, we report that prion infection and prion-mimetic antibodies deplete the phosphoinositide kinase PIKfyve-which controls endolysosomal maturation-from mouse brains, cultured cells, organotypic brain slices, and brains of Creutzfeldt-Jakob disease victims. We found that PIKfyve is acylated by the acyltransferases zDHHC9 and zDHHC21, whose juxtavesicular topology is disturbed by prion infection, resulting in PIKfyve deacylation and rapid degradation, as well as endolysosomal hypertrophy and activation of TFEB-dependent lysosomal enzymes. A protracted unfolded protein response (UPR), typical of prion diseases, also induced PIKfyve deacylation and degradation. Conversely, UPR antagonists restored PIKfyve levels in prion-infected cells. Overexpression of zDHHC9 and zDHHC21, administration of the antiprion polythiophene LIN5044, or supplementation with the PIKfyve reaction product PI(3,5)P2 suppressed prion-induced vacuolation and restored lysosomal homeostasis. Thus, PIKfyve emerges as a central mediator of vacuolation and neurotoxicity in prion diseases.
    Keywords:  neurodegeneration; palmitoylation; prion; spongiosis; unfolded protein response
    DOI:  https://doi.org/10.15252/emmm.202114714
  12. J Biol Chem. 2021 Jul 20. pii: S0021-9258(21)00791-2. [Epub ahead of print] 100989
    Insulin-induced genes INSIG1 and INSIG2 mediate oxysterol-dependent activation of the PERK/eIF2α/ATF4 axis.
    Yuichi Watanabe, Takashi Sasaki, Shoko Miyoshi, Makoto Shimizu, Yoshio Yamauchi, Ryuichiro Sato.
      Insulin-induced genes (INSIGs) encode endoplasmic reticulum (ER)-resident proteins that regulate intracellular cholesterol metabolism. Oxysterols are oxygenated derivatives of cholesterol, some of which orchestrate lipid metabolism via interaction with INSIGs. Recently, it was reported that expression of activating transcription factor-4 (ATF4) was induced by certain oxysterols; the precise of mechanism is unclear. Herein, we show that INSIGs mediate ATF4 upregulation upon interaction with oxysterol. Oxysterols that possess a high affinity for INSIG, such as 27- and 25-hydroxycholesterol (25HC), markedly induced the increase of ATF4 protein when compared with other oxysterols. In addition, ATF4 upregulation by these oxysterols was attenuated in INSIG1/2-deficient CHO cells and was recovered by either INSIG1 or INSIG2 rescue. Mechanistic studies revealed that the binding of 25HC to INSIG is critical for increased ATF4 protein via activation of PERK and eIF2α. Knockout of INSIG1 or INSIG2 in human hepatoma Huh7 cells attenuated ATF4 protein upregulation, indicating that only one of the endogenous INSIGs, unlike overexpression of intrinsic INSIG1 or INSIG2, was insufficient for ATF4 induction. Furthermore, ATF4 proactively upregulated the cell death inducible genes expression, such as Chop, Chac1, and Trb3, thereby markedly reducing cell viability with 25-hydroxycholesterol. These findings support a model whereby that INSIGs sense an increase in oxysterol in the ER and induce an increase of ATF4 protein via the PERK/eIF2α pathway, thereby promoting cell death.
    Keywords:  activating transcription factor-4 (ATF4); cell death; endoplasmic reticulum stress (ER stress); eukaryotic initiation factor 2 (eIF2); oxysterol; sterol; stress response
    DOI:  https://doi.org/10.1016/j.jbc.2021.100989
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