bims-unfpre Biomed News
on Unfolded protein response
Issue of 2024–07–28
eleven papers selected by
Susan Logue, University of Manitoba
  1. ATM facilitates autophagy and protects against oxidative stress and apoptosis in response to ER stress in vitro.
  2. Melatonin regulates endoplasmic reticulum stress in diverse pathophysiological contexts: A comprehensive mechanistic review.
  3. IRE1/JNK Is the Leading UPR Pathway in 6-OHDA-Induced Degeneration of Differentiated SH-SY5Y Cells.
  4. REEP5 mediates the function of CLEC5A to alleviate myocardial infarction by inhibiting endoplasmic reticulum stress-induced apoptosis.
  5. Cepharanthine triggers ferroptosis through inhibition of NRF2 for robust ER stress against lung cancer.
  6. Dantrolene corrects cellular disease features of Darier disease and may be a novel treatment.
  7. Exercise mitigates reductive stress-induced cardiac remodeling in mice.
  8. ER-transiting bacterial toxins amplify STING innate immune responses and elicit ER stress.
  9. PKR Mediates the Mitochondrial Unfolded Protein Response through Double-Stranded RNA Accumulation under Mitochondrial Stress.
  10. Endoplasmic reticulum unfolded protein response transcriptional targets of XBP-1s mediate rescue from tauopathy.
  11. Combined inhibition of EZH2 and CDK4/6 perturbs endoplasmic reticulum-mitochondrial homeostasis and increases antitumor activity against glioblastoma.
  1. Biochem Biophys Res Commun. 2024 Jul 18. pii: S0006-291X(24)00958-6. [Epub ahead of print]732 150422
    ATM facilitates autophagy and protects against oxidative stress and apoptosis in response to ER stress in vitro.
    Danélle Bester, Marguerite Blignaut, Barbara Huisamen.
      The endoplasmic reticulum (ER) responds to cellular stress by initiating an unfolded protein response (UPR) that mitigates misfolded protein accumulation by promoting protein degradation pathways. Chronic ER stress leads to UPR-mediated apoptosis and is a common underlying feature of various diseases, highlighting the modulators of the UPR as attractive targets for therapeutic intervention. Ataxia-telangiectasia mutated protein kinase (ATM) is a stress-responsive kinase that initiates autophagy in response to reactive oxygen species (ROS), and ATM deficiency is associated with increased ER stress markers in vitro. However, whether ATM participates in the UPR remains unclear. In this in vitro study, a novel role for ATM in the ER stress response is described using the well-characterized HEK293 cells treated with the common ER stress-inducing agent, tunicamycin, with and without the potent ATM inhibitor, KU-60019. We show for the first time that ATM is activated in a time-dependent manner downstream of UPR initiation in response to tunicamycin treatment. Furthermore, we demonstrate that ATM is required for p62-bound protein cargo degradation through the autophagy pathway in response to ER stress. Lastly, our data suggest a protective role for ATM in ER stress-mediated oxidative stress and mitochondrial apoptosis. Taken together, we highlight ATM as a potential novel drug target in ER stress-related diseases.
    Keywords:  ATM; Apoptosis; Autophagy; ER stress; Oxidative stress; UPR
    DOI:  https://doi.org/10.1016/j.bbrc.2024.150422
  2. J Cell Physiol. 2024 Jul 22. e31383
    Melatonin regulates endoplasmic reticulum stress in diverse pathophysiological contexts: A comprehensive mechanistic review.
    Luiz Gustavo de Almeida Chuffa, Fábio Rodrigues Ferreira Seiva, Henrique S Silveira, Roberta Carvalho Cesário, Karolina da Silva Tonon, Vinicius Augusto Simão, Debora Aparecida P C Zuccari, Russel J Reiter.
      The endoplasmic reticulum (ER) is crucial for protein quality control, and disruptions in its function can lead to various diseases. ER stress triggers an adaptive response called the unfolded protein response (UPR), which can either restore cellular homeostasis or induce cell death. Melatonin, a safe and multifunctional compound, shows promise in controlling ER stress and could be a valuable therapeutic agent for managing the UPR. By regulating ER and mitochondrial functions, melatonin helps maintain cellular homeostasis via reduction of oxidative stress, inflammation, and apoptosis. Melatonin can directly or indirectly interfere with ER-associated sensors and downstream targets of the UPR, impacting cell death, autophagy, inflammation, molecular repair, among others. Crucially, this review explores the mechanistic role of melatonin on ER stress in various diseases including liver damage, neurodegeneration, reproductive disorders, pulmonary disease, cardiomyopathy, insulin resistance, renal dysfunction, and cancer. Interestingly, while it alleviates the burden of ER stress in most pathological contexts, it can paradoxically stimulate ER stress in cancer cells, highlighting its intricate involvement in cellular homeostasis. With numerous successful studies using in vivo and in vitro models, the continuation of clinical trials is imperative to fully explore melatonin's therapeutic potential in these conditions.
    Keywords:  apoptosis; cell fate; endoplasmic reticulum stress; melatonin; pathological disorders
    DOI:  https://doi.org/10.1002/jcp.31383
  3. Int J Mol Sci. 2024 Jul 12. pii: 7679. [Epub ahead of print]25(14):
    IRE1/JNK Is the Leading UPR Pathway in 6-OHDA-Induced Degeneration of Differentiated SH-SY5Y Cells.
    Natalia Siwecka, Grzegorz Galita, Zuzanna Granek, Wojciech Wiese, Ireneusz Majsterek, Wioletta Rozpędek-Kamińska.
      Parkinson's disease (PD) is a neurodegenerative disorder which affects dopaminergic neurons of the midbrain. Accumulation of α-synuclein or exposure to neurotoxins like 6-hydroxydopamine (6-OHDA) induces endoplasmic reticulum (ER) stress along with the unfolded protein response (UPR), which executes apoptosis via activation of PERK/CHOP or IRE1/JNK signaling. The present study aimed to determine which of these pathways is a major contributor to neurodegeneration in an 6-OHDA-induced in vitro model of PD. For this purpose, we have applied pharmacological PERK and JNK inhibitors (AMG44 and JNK V) in differentiated SH-SY5Y cells exposed to 6-OHDA. Inhibition of PERK and JNK significantly decreased genotoxicity and improved mitochondrial respiration, but only JNK inhibition significantly increased cell viability. Gene expression analysis revealed that the effect of JNK inhibition was dependent on a decrease in MAPK10 and XBP1 mRNA levels, whereas inhibition of either PERK or JNK significantly reduced the expression of DDIT3 mRNA. Western blot has shown that JNK inhibition strongly induced the XBP1s protein, and inhibition of each pathway attenuated the phosphorylation of eIF2α and JNK, as well as the expression of CHOP. Collectively, our data suggests that targeting the IRE1/JNK pathway of the UPR is a more effective option for PD treatment as it simultaneously affects more than one pro-apoptotic pathway.
    Keywords:  6-OHDA; ER stress; IRE1; JNK; PERK; Parkinson’s disease; neurodegeneration; unfolded protein response
    DOI:  https://doi.org/10.3390/ijms25147679
  4. BMC Cardiovasc Disord. 2024 Jul 23. 24(1): 382
    REEP5 mediates the function of CLEC5A to alleviate myocardial infarction by inhibiting endoplasmic reticulum stress-induced apoptosis.
    Xin Wang, Limin Sun.
      MI (myocardial infarction) often triggers severe heart failure and is one of the leading causes of death worldwide. Receptor expression-enhancing protein 5 (REEP5), a member of REEPs, acts as regulators of endoplasmic reticulum (ER) affecting cardiac functions. Based on GSE114695 profile data, REEP5 was decreased in the left ventricle of MI mice. However, its role and potential mechanism in MI remain to be investigated. In the present study, the mouse MI model was established by ligation of the left anterior descending artery. REEP5 expression was downregulated in the infarct penumbra area of MI mice. Next, its role during MI was explored by gain-of-function. Interestingly, REEP5 overexpression improved left ventricular function of mice with MI, accompanied with reduced infarct size. In cardiomyocytes, REEP5 overexpression inhibited ER stress, accompanied with repressive phosphorylation of PERK and IRE1α, and the decreased nuclear translocation of ATF6. Subsequently, REEP5 overexpression downregulated the levels of Chop and cleaved caspase-12, further alleviating ER stress-induced apoptosis, which was consistent with the in vivo results. Moreover, REEP5 was found to bind to C-type lectin member 5 A (CLEC5A), a protein that triggers cardiac dysfunction. CLEC5A, whose expression was elevated in hypoxia-induced cell models, led to cardiomyocyte apoptosis. Noteworthily, REEP5 overexpression markedly abolished the effects of CLEC5A on ER stress-induced apoptosis. Taken together, REEP5 mediated the function of CLEC5A to relieve MI via inhibiting ER stress-induced apoptosis in vivo and in vitro. REEP5 may be a promising target for treating MI.
    Keywords:  Apoptosis; CLEC5A; Endoplasmic reticulum stress; Myocardial infarction; REEP5
    DOI:  https://doi.org/10.1186/s12872-024-04018-3
  5. Eur J Pharmacol. 2024 Jul 20. pii: S0014-2999(24)00528-4. [Epub ahead of print]979 176839
    Cepharanthine triggers ferroptosis through inhibition of NRF2 for robust ER stress against lung cancer.
    Xiao-Feng Bai, Jun Hu, Mei-Fang Wang, Liu-Gen Li, Ning Han, Hansheng Wang, Nan-Nan Chen, Yu-Jie Gao, Hui You, Xiao Wang, Xiang Xu, Ting-Ting Yu, Tong-Fei Li, Tao Ren.
       BACKGROUND: Severe endoplasmic reticulum (ER) stress elicits apoptosis to suppress lung cancer. Our previous research identified that Cepharanthine (CEP), a kind of phytomedicine, possessed powerful anti-cancer efficacy, for which the underlying mechanism was still uncovered. Herein, we investigated how CEP induced ER stress and worked against lung cancer.
    METHODS: The differential expression genes (DEGs) and enrichment were detected by RNA-sequence. The affinity of CEP and NRF2 was analyzed by cellular thermal shift assay (CETSA) and molecular docking. The function assay of lung cancer cells was measured by western blots, flow cytometry, immunofluorescence staining, and ferroptosis inhibitors.
    RESULTS: CEP treatment enriched DEGs in ferroptosis and ER stress. Further analysis demonstrated the target was NRF2. In vitro and in vivo experiments showed that CEP induced obvious ferroptosis, as characterized by the elevated iron ions, ROS, COX-2 expression, down-regulation of GPX4, and atrophic mitochondria. Moreover, enhanced Grp78, CHOP expression, β-amyloid mass, and disappearing parallel stacked structures of ER were observed in CEP group, suggesting ER stress was aroused. CEP exhibited excellent anti-lung cancer efficacy, as evidenced by the increased apoptosis, reduced proliferation, diminished cell stemness, and prominent inhibition of tumor grafts in animal models. Furthermore, the addition of ferroptosis inhibitors weakened CEP-induced ER stress and apoptosis.
    CONCLUSION: In summary, our findings proved CEP drives ferroptosis through inhibition of NRF2 for induction of robust ER stress, thereby leading to apoptosis and attenuated stemness of lung cancer cells. The current work presents a novel mechanism for the anti-tumor efficacy of the natural compound CEP.
    Keywords:  Cepharanthine (CEP); ER stress; Ferroptosis; KEAP1/NRF2; Lung cancer
    DOI:  https://doi.org/10.1016/j.ejphar.2024.176839
  6. EMBO Mol Med. 2024 Jul 26.
    Dantrolene corrects cellular disease features of Darier disease and may be a novel treatment.
    Matthew Hunt, Nuoqi Wang, Naricha Pupinyo, Philip Curman, Monica Torres, William Jebril, Maria Chatzinikolaou, Julie Lorent, Gilad Silberberg, Ritu Bansal, Teresa Burner, Jing Zhou, Susanne Kimeswenger, Wolfram Hoetzenecker, Keith Choate, Etty Bachar-Wikstrom, Jakob D Wikstrom.
      Darier disease (DD) is a rare severe acantholytic skin disease caused by mutations in the ATP2A2 gene that encodes for the sarco/endoplasmic reticulum calcium ATPase isoform 2 (SERCA2). SERCA2 maintains endoplasmic reticulum calcium homeostasis by pumping calcium into the ER, critical for regulating cellular calcium dynamics and cellular function. To date, there is no treatment that specifically targets the disease mechanisms in DD. Dantrolene sodium (Dl) is a ryanodine receptor antagonist that inhibits calcium release from ER to increase ER calcium levels and is currently used for non-dermatological indications. In this study, we first identified dysregulated genes and molecular pathways in DD patient skin, demonstrating downregulation of cell adhesion and calcium homeostasis pathways, as well as upregulation of ER stress and apoptosis. We then show in various in vitro models of DD and SERCA2 inhibition that Dl aided in the retention of ER calcium and promoted cell adhesion. In addition, Dl treatment reduced ER stress and suppressed apoptosis. Our findings suggest that Dl specifically targets pathogenic mechanisms of DD and may be a potential treatment.
    Keywords:  Cell Adhesion; Dantrolene; Darier Disease; ER Calcium; UPR
    DOI:  https://doi.org/10.1038/s44321-024-00104-3
  7. Redox Biol. 2024 Jul 04. pii: S2213-2317(24)00241-6. [Epub ahead of print]75 103263
    Exercise mitigates reductive stress-induced cardiac remodeling in mice.
    Arun Jyothidasan, Sini Sunny, Asokan Devarajan, Aniqa Sayed, John Kofi Afortude, Brian Dalley, Vivek Nanda, Steven Pogwizd, Silvio H Litovsky, Joel D Trinity, Matthew Might, Namakkal S Rajasekaran.
      The endoplasmic reticulum (ER) regulates protein folding and maintains proteostasis in cells. We observed that the ER transcriptome is impaired during chronic reductive stress (RS) in cardiomyocytes. Here, we hypothesized that a prolonged moderate treadmill exercise mitigates the RS-induced ER dysfunction and cardiac remodeling in cardiac-specific constitutively active Nrf2 mice (CaNrf2-TG). RNA sequencing showed notable alterations in the ER transcriptome of TG hearts at 4, 12, and 24 weeks (16, 28, and 35 genes, respectively). Notably, the downregulation of ER genes was significant at 12 weeks, and further pronounced at 24 weeks, at which the cardiac pathology is evident. We also observed increased levels of ubiquitinated proteins in CaNrf2-TG hearts across all ages, along with VCP, a marker of ERAD function, at 24 weeks. These findings indicate that constitutive Nrf2 activation and RS impair protein-folding activity and augments ERAD function over time. Exercise intervention for 20 weeks (beginning at 6 weeks of age), reduced cardiomyocyte hypertrophy (from 448 μm2 to 280 μm2) in TG mice, through adaptive remodeling, and preserved the cardiac function. However, while exercise did not influence antioxidants or ER stress protein levels, it significantly improved ERAD function and autophagy flux (LC-I to LC-II) in the TG-EXE hearts. Collectively, our findings underscore the prophylactic potential of exercise in mitigating RS-associated pathology, highlighting its essential role in maintaining cellular proteostasis through ER-independent mechanisms.
    Keywords:  Cardiac hypertrophy; ER stress; Exercise; Nrf2 signaling; Oxidative stress; Proteostasis; Reductive stress
    DOI:  https://doi.org/10.1016/j.redox.2024.103263
  8. Infect Immun. 2024 Jul 26. e0030024
    ER-transiting bacterial toxins amplify STING innate immune responses and elicit ER stress.
    Catherine Schlenker, Katharina Richard, Sofia Skobelkina, R Paige Mathena, Darren J Perkins.
      The cGAS/STING sensor system drives innate immune responses to intracellular microbial double-stranded DNA (dsDNA) and bacterial cyclic nucleotide second messengers (e.g., c-di-AMP). STING-dependent cell-intrinsic responses can increase resistance to microbial infection and speed pathogen clearance. Correspondingly, STING activation and signaling are known to be targeted for suppression by effectors from several bacterial pathogens. Whether STING responses are also positively regulated through sensing of specific bacterial effectors is less clear. We find that STING activation through dsDNA, by its canonical ligand 2'-3' cGAMP, or the small molecule DMXAA is potentiated following intracellular delivery of the AB5 toxin family member pertussis toxin from Bordetella pertussis or the B subunit of cholera toxin from Vibrio cholerae. Entry of pertussis toxin or cholera toxin B into mouse macrophages triggers markers of endoplasmic reticulum (ER) stress and enhances ligand-dependent STING responses at the level of STING receptor activation in a manner that is independent of toxin enzymatic activity. Our results provide an example in which STING responses integrate information about the presence of relevant ER-transiting bacterial toxins into the innate inflammatory response and may help to explain the in vivo adjuvant effects of catalytically inactive toxins.
    Keywords:  ADP ribosylation; GPCR; STING; cGAS; cholera toxin; endoplasmic reticulum; pertussis toxin; type I interferon
    DOI:  https://doi.org/10.1128/iai.00300-24
  9. Int J Mol Sci. 2024 Jul 15. pii: 7738. [Epub ahead of print]25(14):
    PKR Mediates the Mitochondrial Unfolded Protein Response through Double-Stranded RNA Accumulation under Mitochondrial Stress.
    Fedho Kusuma, Soyoung Park, Kim Anh Nguyen, Rosalie Elvira, Duckgue Lee, Jaeseok Han.
      Mitochondrial stress, resulting from dysfunction and proteostasis disturbances, triggers the mitochondrial unfolded protein response (UPRMT), which activates gene encoding chaperones and proteases to restore mitochondrial function. Although ATFS-1 mediates mitochondrial stress UPRMT induction in C. elegans, the mechanisms relaying mitochondrial stress signals to the nucleus in mammals remain poorly defined. Here, we explored the role of protein kinase R (PKR), an eIF2α kinase activated by double-stranded RNAs (dsRNAs), in mitochondrial stress signaling. We found that UPRMT does not occur in cells lacking PKR, indicating its crucial role in this process. Mechanistically, we observed that dsRNAs accumulate within mitochondria under stress conditions, along with unprocessed mitochondrial transcripts. Furthermore, we demonstrated that accumulated mitochondrial dsRNAs in mouse embryonic fibroblasts (MEFs) deficient in the Bax/Bak channels are not released into the cytosol and do not induce the UPRMT upon mitochondrial stress, suggesting a potential role of the Bax/Bak channels in mediating the mitochondrial stress response. These discoveries enhance our understanding of how cells maintain mitochondrial integrity, respond to mitochondrial dysfunction, and communicate stress signals to the nucleus through retrograde signaling. This knowledge provides valuable insights into prospective therapeutic targets for diseases associated with mitochondrial stress.
    Keywords:  PKR; UPRMT; integrated stress response; mitochondrial dsRNAs; mitochondrial stress
    DOI:  https://doi.org/10.3390/ijms25147738
  10. Commun Biol. 2024 Jul 25. 7(1): 903
    Endoplasmic reticulum unfolded protein response transcriptional targets of XBP-1s mediate rescue from tauopathy.
    Sarah M Waldherr, Marina Han, Aleen D Saxton, Taylor A Vadset, Pamela J McMillan, Jeanna M Wheeler, Nicole F Liachko, Brian C Kraemer.
      Pathological tau disrupts protein homeostasis (proteostasis) within neurons in Alzheimer's disease (AD) and related disorders. We previously showed constitutive activation of the endoplasmic reticulum unfolded protein response (UPRER) transcription factor XBP-1s rescues tauopathy-related proteostatic disruption in a tau transgenic Caenorhabditis elegans (C. elegans) model of human tauopathy. XBP-1s promotes clearance of pathological tau, and loss of function of the ATF-6 branch of the UPRER prevents XBP-1s rescue of tauopathy in C. elegans. We conducted transcriptomic analysis of tau transgenic and xbp-1s transgenic C. elegans and found 116 putative target genes significantly upregulated by constitutively active XBP-1s. Among these were five candidate XBP-1s target genes with human orthologs and a previously known association with ATF6 (csp-1, dnj-28, hsp-4, ckb-2, and lipl-3). We examined the functional involvement of these targets in XBP-1s-mediated tauopathy suppression and found loss of function in any one of these genes completely disrupts XBP-1s suppression of tauopathy. Further, we demonstrate upregulation of HSP-4, C. elegans BiP, partially rescues tauopathy independent of other changes in the transcriptional network. Understanding how the UPRER modulates pathological tau accumulation will inform neurodegenerative disease mechanisms and direct further study in mammalian systems with the long-term goal of identifying therapeutic targets in human tauopathies.
    DOI:  https://doi.org/10.1038/s42003-024-06570-2
  11. NPJ Precis Oncol. 2024 Jul 25. 8(1): 156
    Combined inhibition of EZH2 and CDK4/6 perturbs endoplasmic reticulum-mitochondrial homeostasis and increases antitumor activity against glioblastoma.
    Thomas Freitag, Philipp Kaps, Justus Ramtke, Sarah Bertels, Emily Zunke, Björn Schneider, Anne-Sophie Becker, Dirk Koczan, Daniel Dubinski, Thomas M Freiman, Felix Wittig, Burkhard Hinz, Mike-Andrew Westhoff, Hannah Strobel, Franziska Meiners, Daniel Wolter, Nadja Engel, Sascha Troschke-Meurer, Wendy Bergmann-Ewert, Susanne Staehlke, Annabell Wolff, Florian Gessler, Christian Junghanss, Claudia Maletzki.
      He, we show that combined use of the EZH2 inhibitor GSK126 and the CDK4/6 inhibitor abemaciclib synergistically enhances antitumoral effects in preclinical GBM models. Dual blockade led to HIF1α upregulation and CalR translocation, accompanied by massive impairment of mitochondrial function. Basal oxygen consumption rate, ATP synthesis, and maximal mitochondrial respiration decreased, confirming disrupted endoplasmic reticulum-mitochondrial homeostasis. This was paralleled by mitochondrial depolarization and upregulation of the UPR sensors PERK, ATF6α, and IRE1α. Notably, dual EZH2/CDK4/6 blockade also reduced 3D-spheroid invasion, partially inhibited tumor growth in ovo, and led to impaired viability of patient-derived organoids. Mechanistically, this was due to transcriptional changes in genes involved in mitotic aberrations/spindle assembly (Rb, PLK1, RRM2, PRC1, CENPF, TPX2), histone modification (HIST1H1B, HIST1H3G), DNA damage/replication stress events (TOP2A, ATF4), immuno-oncology (DEPDC1), EMT-counterregulation (PCDH1) and a shift in the stemness profile towards a more differentiated state. We propose a dual EZH2/CDK4/6 blockade for further investigation.
    DOI:  https://doi.org/10.1038/s41698-024-00653-3
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