bims-unfpre Biomed News
on Unfolded protein response
Issue of 2022–11–20
seven papers selected by
Susan Logue, University of Manitoba
  1. iASPP suppression mediates terminal UPR and improves BRAF-inhibitor sensitivity of colon cancers.
  2. IRE-1 endoribonuclease activity declines early in C. elegans adulthood and is not rescued by reduced reproduction.
  3. Endoplasmic reticulum stress and lipids in health and diseases.
  4. PERK/ATF4-dependent expression of the stress response protein REDD1 promotes pro-inflammatory cytokine expression in the heart of obese mice.
  5. Agr2-associated ER stress promotes adherent-invasive E. coli dysbiosis and triggers CD103+ dendritic cell IL-23-dependent ileocolitis.
  6. 4-phenylbutyric acid-Identity crisis; can it act as a translation inhibitor?
  7. The stress-inducible ER chaperone GRP78/BiP is upregulated during SARS-CoV-2 infection and acts as a pro-viral protein.
  1. Cell Death Differ. 2022 Nov 15.
    iASPP suppression mediates terminal UPR and improves BRAF-inhibitor sensitivity of colon cancers.
    Shanliang Zheng, Xingwen Wang, Hao Liu, Dong Zhao, Qingyu Lin, Qinghua Jiang, Li Li, Ying Hu.
      Unfolded protein response (UPR) signaling is activated under endoplasmic reticulum (ER) stress, an emerging cancer hallmark, leading to either adaptive survival or cell death, while the mechanisms underlying adaptation-death switch remain poorly understood. Here, we examined whether oncogene iASPP regulates the switch and how the mechanisms can be used in colon cancer treatment. iASPP is downregulated when cells undergo transition from adaptation to death during therapy-induced ER stress. Blocking iASPP's downregulation attenuates stress-induced cell death. Mechanistically, Hu-antigen R (HuR)-mediated stabilization of iASPP mRNA and subsequent iASPP protein production is significantly impaired with prolonged ER stress, which facilitates the degradation of GRP78, a key regulator of the UPR, in the cytosol. Because iASPP competes with GRP78 in binding the ER-resident E3 ligase RNF185, and tips the balance in favor of cell death. Positive correlation between the levels of HuR, iASPP, and GRP78 are detectable in colon cancer tissues in vivo. Genetic inhibition of iASPP/GRP78 or chemical inhibition of HuR not only inhibits tumor growth, but also sensitizes colon cancer cells' responses to BRAF inhibitor-induced ER stress and cell death. This study provides mechanistic insights into the switch between adaptation and death during ER stress, and also identifies a potential strategy to improve BRAF-inhibitor efficiency in colon cancers.
    DOI:  https://doi.org/10.1038/s41418-022-01086-w
  2. Front Aging. 2022 ;3 1044556
    IRE-1 endoribonuclease activity declines early in C. elegans adulthood and is not rescued by reduced reproduction.
    Evandro A De-Souza, Nadia Cummins, Rebecca C Taylor.
      The proteome of a cell helps to define its functional specialization. Most proteins must be translated and properly folded to ensure their biological function, but with aging, animals lose their ability to maintain a correctly folded proteome. This leads to the accumulation of protein aggregates, decreased stress resistance, and the onset of age-related disorders. The unfolded protein response of the endoplasmic reticulum (UPRER) is a central protein quality control mechanism, the function of which is known to decline with age. Here, we show that age-related UPRER decline in Caenorhabditis elegans occurs at the onset of the reproductive period and is caused by a failure in IRE-1 endoribonuclease activities, affecting both the splicing of xbp-1 mRNA and regulated Ire1 dependent decay (RIDD) activity. Animals with a defect in germline development, previously shown to rescue the transcriptional activity of other stress responses during aging, do not show restored UPRER activation with age. This underlines the mechanistic difference between age-associated loss of UPRER activation and that of other stress responses in this system, and uncouples reproductive status from the activity of somatic maintenance pathways. These observations may aid in the development of strategies that aim to overcome the proteostasis decline observed with aging.
    Keywords:  C. elegans; IRE1; UPR; aging; cell stress; proteostasis; stress response; unfolded protein response
    DOI:  https://doi.org/10.3389/fragi.2022.1044556
  3. Prog Lipid Res. 2022 Nov 13. pii: S0163-7827(22)00053-4. [Epub ahead of print]89 101198
    Endoplasmic reticulum stress and lipids in health and diseases.
    Cenk Celik, Stella Yue Ting Lee, Wei Sheng Yap, Guillaume Thibault.
      The endoplasmic reticulum (ER) is a complex and dynamic organelle that regulates many cellular pathways, including protein synthesis, protein quality control, and lipid synthesis. When one or multiple ER roles are dysregulated and saturated, the ER enters a stress state, which, in turn, activates the highly conserved unfolded protein response (UPR). By sensing the accumulation of unfolded proteins or lipid bilayer stress (LBS) at the ER, the UPR triggers pathways to restore ER homeostasis and eventually induces apoptosis if the stress remains unresolved. In recent years, it has emerged that the UPR works intimately with other cellular pathways to maintain lipid homeostasis at the ER, and so does at cellular levels. Lipid distribution, along with lipid anabolism and catabolism, are tightly regulated, in part, by the ER. Dysfunctional and overwhelmed lipid-related pathways, independently or in combination with ER stress, can have reciprocal effects on other cellular functions, contributing to the development of diseases. In this review, we summarize the current understanding of the UPR in response to proteotoxic stress and LBS and the breadth of the functions mitigated by the UPR in different tissues and in the context of diseases.
    Keywords:  Cancer; Diabetes; Endoplasmic reticulum stress; Fatty liver; Immune response; Lipid bilayer stress; Lipid homeostasis; Lipotoxicity; Metabolic diseases; Unfolded protein response
    DOI:  https://doi.org/10.1016/j.plipres.2022.101198
  4. Am J Physiol Endocrinol Metab. 2022 Nov 16.
    PERK/ATF4-dependent expression of the stress response protein REDD1 promotes pro-inflammatory cytokine expression in the heart of obese mice.
    Shaunaci A Stevens, Maria K Gonzalez Aguiar, Allyson L Toro, Esma I Yerlikaya, Siddharth Sunilkumar, Ashley M VanCleave, Jessica Pfleger, Elisa A Bradley, Scot R Kimball, Michael D Dennis.
      Endoplasmic reticulum (ER) stress and inflammation are hallmarks of myocardial impairment. Here we investigated a role for the stress response protein REDD1 as a molecular link between ER stress and inflammation in cardiomyocytes. In mice fed a high-fat high-sucrose (HFHS, 42% kcal fat, 34% sucrose by weight) diet for 12 weeks, REDD1 expression in the heart was increased in coordination with markers of ER stress and inflammation. In human AC16 cardiomyocytes exposed to either hyperglycemic conditions or the saturated fatty acid palmitate, REDD1 expression was increased coincident with ER stress and upregulated expression of the pro-inflammatory cytokines IL-1β, IL-6, and TNF⍺. In cardiomyocytes exposed to hyperglycemic/hyperlipidemic conditions, pharmacological inhibition of the ER kinase PERK or knockdown of the transcription factor ATF4 prevented the increase in REDD1 expression. REDD1 deletion reduced pro-inflammatory cytokine expression in both cardiomyocytes exposed to hyperglycemic/hyperlipidemic conditions and in the hearts of obese mice. Overall, the findings support a model wherein HFHS diet contributes to the development of inflammation in cardiomyocytes by promoting REDD1 expression via activation of a PERK/ATF4 signaling axis.
    Keywords:  DDIT4; ER stress; diabetes; inflammation; obesity
    DOI:  https://doi.org/10.1152/ajpendo.00238.2022
  5. Cell Rep. 2022 Nov 15. pii: S2211-1247(22)01508-X. [Epub ahead of print]41(7): 111637
    Agr2-associated ER stress promotes adherent-invasive E. coli dysbiosis and triggers CD103+ dendritic cell IL-23-dependent ileocolitis.
    Monica Viladomiu, Manirath Khounlotham, Belgin Dogan, Svetlana F Lima, Ahmed Elsaadi, Emre Cardakli, Jim G Castellanos, Charles Ng, Jeremy Herzog, Alexi A Schoenborn, Melissa Ellermann, Bo Liu, Shiying Zhang, Ajay S Gulati, R Balfour Sartor, Kenneth W Simpson, Steven M Lipkin, Randy S Longman.
      Endoplasmic reticulum (ER) stress is associated with Crohn's disease (CD), but its impact on host-microbe interaction in disease pathogenesis is not well defined. Functional deficiency in the protein disulfide isomerase anterior gradient 2 (AGR2) has been linked with CD and leads to epithelial cell ER stress and ileocolitis in mice and humans. Here, we show that ileal expression of AGR2 correlates with mucosal Enterobactericeae abundance in human inflammatory bowel disease (IBD) and that Agr2 deletion leads to ER-stress-dependent expansion of mucosal-associated adherent-invasive Escherichia coli (AIEC), which drives Th17 cell ileocolitis in mice. Mechanistically, our data reveal that AIEC-induced epithelial cell ER stress triggers CD103+ dendritic cell production of interleukin-23 (IL-23) and that IL-23R is required for ileocolitis in Agr2-/- mice. Overall, these data reveal a specific and reciprocal interaction of the expansion of the CD pathobiont AIEC with ER-stress-associated ileocolitis and highlight a distinct cellular mechanism for IL-23-dependent ileocolitis.
    Keywords:  AIEC; Agr2; CP: Immunology; CP: Microbiology; ER stress; IL-23; Th17; ileitis
    DOI:  https://doi.org/10.1016/j.celrep.2022.111637
  6. Aging Cell. 2022 Nov 14. e13738
    4-phenylbutyric acid-Identity crisis; can it act as a translation inhibitor?
    Daniel Stein, Zeev Slobodnik, Benjamin Tam, Monica Einav, Barak Akabayov, Shimon Berstein, Debra Toiber.
      Loss of proteostasis can occur due to mutations, the formation of aggregates, or general deficiency in the correct translation and folding of proteins. These phenomena are commonly observed in pathologies, but most significantly, loss of proteostasis characterizes aging. This loss leads to the chronic activation of stress responses and has a generally deleterious impact on the organism. While finding molecules that can alleviate these symptoms is an important step toward solutions for these conditions, some molecules might be mischaracterized on the way. 4-phenylbutyric acid (4PBA) is known for its role as a chemical chaperone that helps alleviate endoplasmic reticulum (ER) stress, yet a scan of the literature reveals that no biochemical or molecular experiments have shown any protein refolding capacity. Here, we show that 4PBA is a conserved weak inhibitor of mRNA translation, both in vitro and in cellular systems, and furthermore-it does not promote protein folding nor prevents aggregation. 4PBA possibly alleviates proteostatic or ER stress by inhibiting protein synthesis, allowing the cells to cope with misfolded proteins by reducing the protein load. Better understanding of 4PBA biochemical mechanisms will improve its usage in basic science and as a drug in different pathologies, also opening new venues for the treatment of different diseases.
    Keywords:  4PBA; Proteostasis; chemical chaperone; protein synthesis; translation inhibition; unfolded protein response
    DOI:  https://doi.org/10.1111/acel.13738
  7. Nat Commun. 2022 Nov 14. 13(1): 6551
    The stress-inducible ER chaperone GRP78/BiP is upregulated during SARS-CoV-2 infection and acts as a pro-viral protein.
    Woo-Jin Shin, Dat P Ha, Keigo Machida, Amy S Lee.
      
    DOI:  https://doi.org/10.1038/s41467-022-34065-3
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