bims-unfpre Biomed News
on Unfolded protein response
Issue of 2019‒08‒11
eight papers selected by
Susan Logue
University of Manitoba


  1. Trends Pharmacol Sci. 2019 Jul 31. pii: S0165-6147(19)30140-3. [Epub ahead of print]
    Gonzalez-Teuber V, Albert-Gasco H, Auyeung VC, Papa FR, Mallucci GR, Hetz C.
      Abnormally high levels of misfolded proteins in the endoplasmic reticulum (ER) lumen result in a stress state that contributes to the progression of several pathological conditions including diabetes, cancer, neurodegeneration, and immune dysregulation. ER stress triggers a dynamic signaling pathway known as the unfolded protein response (UPR). The UPR enforces adaptive or cell death programs by integrating information about the intensity and duration of the stress stimuli. Thus, depending on the disease context, ER stress signaling can be beneficial or detrimental. We discuss current efforts to develop small molecules to target distinct components of the UPR, and their possible applications in treating human disease, focusing on neurodegenerative diseases, metabolic disorders, and cancer.
    Keywords:  ER stress; ISR; UPR; drug repurposing; proteostasis; small molecules
    DOI:  https://doi.org/10.1016/j.tips.2019.07.003
  2. Hepatology. 2019 Aug 05.
    Zhou Y, Dong B, Kim KH, Choi S, Sun Z, Wu N, Wu Y, Scott J, Moore DD.
      Hepatic endoplasmic reticulum (ER) stress, whether triggered by intrinsic or extrinsic factors, can be resolved by the unfolded protein response (UPR). Sustained UPR activation leads to cell death and inflammatory response and contributes to liver disease progression. Hepatic tissue macrophages are key players in orchestrating liver inflammation and ER stress can enhance macrophage activation. However, it is not well defined how the interplay between ER stress and inflammation is regulated during hepatic stress response. Here we demonstrate that vitamin D receptor (VDR) activation mitigates hepatic ER stress response, whereas VDR knockout mice undergo persistent UPR activation and apoptosis in response to chemical ER stress inducer. Moreover, VDR deficiency promotes hepatic macrophage infiltration and increases gene expression and systematic levels of proinflammatory cytokines, including IL-1β, IL-6 and Tnfα. VDR expression is induced in hepatic macrophages by ER stress, and VDR plays a dual regulatory role in macrophages, through protecting against ER stress and promoting anti-inflammatory polarization. Co-culture with VDR-activated bone marrow-derived macrophages (BMDMs) suppresses UPR target genes in primary hepatocytes treated with an ER stress inducer. Thus, the immunomodulatory functions of VDR in macrophages are critical in hepatic ER stress resolution in mice. CONCLUSION: VDR signaling in macrophages regulates a shift between proinflammatory and anti-inflammatory activation during ER stress-induced inflammation to promote hepatic ER stress resolution. This article is protected by copyright. All rights reserved.
    Keywords:  Kupffer cell; immunoregulation; inflammation; intercellular crosstalk; stress reliever
    DOI:  https://doi.org/10.1002/hep.30887
  3. J Antibiot (Tokyo). 2019 Aug 09.
    Tashiro E.
      Endoplasmic reticulum (ER) stress and the subsequent adaptive cellular response, termed the unfolded protein response (UPR), have been implicated in several diseases, including cancer. In this review, I present a brief introduction to ER stress and the UPR and then summarize the importance of the IRE1α-XBP1 branch as a target for anticancer drug discovery. In addition, I introduce our approach to the identification of inhibitors against the IRE1α-XBP1 branch from microbial cultures. As a result of our screening, toyocamycin has been identified and toyocamycin showed anticancer activity against multiple myeloma.
    DOI:  https://doi.org/10.1038/s41429-019-0219-3
  4. J Cell Biol. 2019 Aug 06. pii: jcb.201901156. [Epub ahead of print]
    Chen FY, Huang MY, Lin YM, Ho CH, Lin SY, Chen HY, Hung MC, Chen RH.
      The BH3-only pro-apoptotic protein BIK is regulated by the ubiquitin-proteasome system. However, the mechanism of this regulation and its physiological functions remain elusive. Here, we identify Cul5-ASB11 as the E3 ligase targeting BIK for ubiquitination and degradation. ER stress leads to the activation of ASB11 by XBP1s during the adaptive phase of the unfolded protein response, which stimulates BIK ubiquitination, interaction with p97/VCP, and proteolysis. This mechanism of BIK degradation contributes to ER stress adaptation by promoting cell survival. Conversely, genotoxic agents down-regulate this IRE1α-XBP1s-ASB11 axis and stabilize BIK, which contributes in part to the apoptotic response to DNA damage. We show that blockade of this BIK degradation pathway by an IRE1α inhibitor can stabilize a BIK active mutant and increase its anti-tumor activity. Our study reveals that different cellular stresses regulate BIK ubiquitination by ASB11 in opposing directions, which determines whether or not cells survive, and that blocking BIK degradation has the potential to be used as an anti-cancer strategy.
    DOI:  https://doi.org/10.1083/jcb.201901156
  5. Cell Microbiol. 2019 Aug 06. e13094
    Go D, Lee J, Choi JA, Cho SN, Kim SH, Son SH, Song CH.
      Mycobacterium avium, a slow-growing non-tuberculosis mycobacterium, causes fever, diarrhoea, loss of appetite, and weight loss in immunocompromised people. We have proposed that endoplasmic reticulum (ER) stress-mediated apoptosis plays a critical role in removing intracellular mycobacteria. In the present study, we investigated the role of the regulated IRE1-dependent decay (RIDD) pathway in macrophages during M. avium infection based on its role in the regulation of gene expression. The inositol-requiring enzyme 1 (IRE1)/apoptosis signal-regulating kinase 1 (ASK1)/c-Jun N-terminal kinase (JNK) signalling pathway was activated in macrophages after infection with M. avium. The expression of RIDD-associated genes, such as Bloc1s1 and St3gal5, was decreased in M. avium-infected macrophages. Interestingly, M. avium-induced apoptosis was significantly suppressed by pre-treatment with irestatin (inhibitor of IRE1α) and 4μ8c (RIDD blocker). Macrophages pre-treated with N-acetyl cysteine (NAC) showed decreased levels of reactive oxygen species (ROS), IRE1α, and apoptosis after M. avium infection. The expression of Bloc1s1 and St3gal5 was increased in NAC-pre-treated macrophages following infection with M. avium. Growth of M. avium was significantly increased in irestatin-, 4μ8c-, and NAC-treated macrophages compared to the control. The data indicate that the ROS-mediated ER stress response induces apoptosis of M. avium-infected macrophages by activating IRE1α-RIDD. Thus, activation of IRE1α suppresses the intracellular survival of M. avium in macrophages.
    Keywords:  Apoptosis; ER stress; IRE1α; Mycobacterium avium; RIDD
    DOI:  https://doi.org/10.1111/cmi.13094
  6. FEBS J. 2019 Aug 06.
    Stolz A, Grumati P.
      The endoplasmic reticulum (ER) is a large and dynamic cellular organelle. ER morphology consists of sheets, tubules, matrixes and contact sites shared with other membranous organelles. The capacity of the ER to fulfil its numerous biological functions depends on its continuous remodeling and the quality control of its proteome. Selective turnover of the ER by autophagy, termed ER-phagy, plays an important role in maintaining ER homeostasis. ER network integrity and turnover rely on specific ER-phagy receptors, which influence and co-ordinate alterations in ER morphology and the degradation of ER contents and membranes via the lysosome, by interacting with the LC3/GABARAP family. In this commentary, we discuss general principles and identify the major players in this recently characterized form of selective autophagy, while simultaneously highlighting open questions in the field. This article is protected by copyright. All rights reserved.
    Keywords:  ER-phagy; autophagy; endoplasmic reticulum; lysosome
    DOI:  https://doi.org/10.1111/febs.15031
  7. Cancer Res. 2019 Aug 07. pii: canres.0054.2019. [Epub ahead of print]
    Zhang Y, Pusch S, Innes J, Sidlauskas K, Ellis M, Lau J, El-Hassan T, Aley N, Launchbury F, Richard-Loendt A, de Boer J, Chen S, Wang L, von Deimling A, Li N, Brandner S.
      Human astrocytomas and oligodendrogliomas are defined by mutations of the metabolic enzymes isocitrate dehydrogenase (IDH) 1 or 2, resulting in the production of the abnormal metabolite D-2 hydroxyglutarate. Here, we studied the effect of mutant IDH on cell proliferation and apoptosis in a glioma mouse model. Tumors were generated by inactivating Pten and p53 in forebrain progenitors and compared with tumors additionally expressing the Idh1 R132H mutation. Idh-mutant cells proliferated less in vitro and mice with Idh-mutant tumors survived significantly longer compared to Idh-wildtype mice. Comparison of micro-RNA and RNA expression profiles of Idh-wildtype and Idh-mutant cells and tumors revealed miR183 was significantly upregulated in IDH-mutant cells. Idh-mutant cells were more sensitive to endoplasmic reticulum (ER) stress, resulting in increased apoptosis and thus reduced cell proliferation and survival. This was mediated by the interaction of miR183 with the 5' untranslated region of Semaphorin3E, downregulating its function as an apoptosis suppressor. In conclusion, we show that mutant Idh1 delays tumorigenesis, and sensitizes tumor cells to ER stress and apoptosis. This may open opportunities for drug treatments targeting the miR183-semaphorin axis.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-19-0054
  8. Cell Death Dis. 2019 Aug 08. 10(8): 595
    Dai H, Shen K, Yang Y, Su X, Luo Y, Jiang Y, Shuai L, Zheng P, Chen Z, Bie P.
      Pancreatic ductal adenocarcinoma (PDAC) is a malignant tumor with very poor prognosis. Therefore, it is important to fully understand the molecular mechanism underlying its occurrence and development. Pumilio RNA-binding family member 1 (PUM1) has been reported to function as an oncogene in ovarian cancer and nonsmall cell lung cancer. However, its role and mechanism in PDAC have not been fully illuminated. Here, we found that the PUM1 protein levels were higher in PDAC tissues than in adjacent tissues and that PUM1 levels were significantly associated with TNM stage and overall survival time, indicating a correlation between high PUM1 expression and poor prognosis in patients with PDAC. In vitro and in vivo assays showed that PUM1 knockdown inhibited cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT), and promoted apoptosis in MIA PaCa-2 and PANC-1 cells. Through cDNA microarrays and ingenuity pathway analysis, we found that the activation of the eIF2 signaling pathway significantly correlated with PUM1 knockdown. These results were further confirmed by the increased levels of key components of the eIF2 signaling pathway, p-PERK, p-EIF2A, and ATF4 in PUM1 knockdown cells. We also found that PUM1 levels have a significant negative correlation with p-PERK levels in PDAC tissues and that PERK overexpression inhibited cell proliferation, migration, invasion, and EMT, and promoted apoptosis in vitro. Moreover, a PERK inhibitor alleviated the effects of PUM1 knockdown on cell proliferation, apoptosis, migration, invasion, and EMT. Taken together, our results revealed that PUM1 knockdown suppressed cell growth, invasion, and metastasis, and promoted apoptosis by activating the PERK/eIF2/ATF4 signaling pathway in PDAC cells. PUM1 could be a potential target to develop pharmaceuticals and novel therapeutic strategies for the treatment of PDAC.
    DOI:  https://doi.org/10.1038/s41419-019-1839-z