bims-unfpre Biomed News
on Unfolded protein response
Issue of 2020‒09‒06
fourteen papers selected by
Susan Logue
University of Manitoba


  1. Cancer Lett. 2020 Aug 31. pii: S0304-3835(20)30442-0. [Epub ahead of print]
    Le Reste PJ, Pineau R, Voutetakis K, Samal J, Jégou G, Lhomond S, Gorman AM, Samali A, Patterson JB, Zeng Q, Pandit A, Aubry M, Soriano N, Etcheverry A, Chatziioannou A, Mosser J, Avril T, Chevet E.
      Glioblastoma multiforme (GBM) is the most severe primary brain cancer. Despite an aggressive treatment comprising surgical resection and radio/chemotherapy, patient's survival post diagnosis remains short. A limitation for success in finding novel improved therapeutic options for such dismal disease partly lies in the lack of a relevant animal model that accurately recapitulates patient disease and standard of care. In the present study, we have developed an immunocompetent GBM model that includes tumor surgery and a radio/chemotherapy regimen resembling the Stupp protocol and we have used this model to test the impact of the pharmacological inhibition of the endoplasmic reticulum (ER) stress sensor IRE1, on treatment efficacy.
    Keywords:  Endoplasmic reticulum; Glioblastoma; IRE1; Unfolded Protein Response
    DOI:  https://doi.org/10.1016/j.canlet.2020.08.028
  2. J Biol Chem. 2020 Sep 04. pii: jbc.REV120.010218. [Epub ahead of print]
    Grandjean JMD, Wiseman RL.
      The unfolded protein response (UPR) plays a central role in regulating endoplasmic reticulum (ER) and global cellular physiology in response to pathologic ER stress. The UPR is comprised of three signaling pathways activated downstream of the ER membrane proteins IRE1, ATF6, and PERK. Once activated, these proteins initiate transcriptional and translational signaling that functions to alleviate ER stress, adapt cellular physiology, and dictate cell fate.  Imbalances in UPR signaling are implicated in the pathogenesis of numerous, etiologically-diverse diseases including many neurodegenerative diseases, protein misfolding diseases, diabetes, ischemic disorders, and cancer. This has led to significant interest in establishing pharmacologic strategies to selectively modulate IRE1, ATF6, or PERK signaling to both ameliorate pathologic imbalances in UPR signaling implicated in these different diseases, and to define the importance of the UPR in diverse cellular and organismal contexts. Recently, there has been significant progress in the identification and characterization of UPR modulating compounds, providing new opportunities to probe the pathologic and potentially therapeutic implications of UPR signaling in human disease. Here, we describe currently available UPR modulating compounds, specifically highlighting the strategies used for their discovery and specific advantages and disadvantages in their application for probing UPR function. Furthermore, we discuss lessons learned from the application of these compounds in cellular and in vivo models to identify favorable compound properties that can help drive the further translational development of selective UPR modulators for human disease.
    Keywords:  endoplasmic reticulum stress (ER stress); proteostasis; small molecule; stress response; unfolded protein response (UPR)
    DOI:  https://doi.org/10.1074/jbc.REV120.010218
  3. Trends Cancer. 2020 Aug 26. pii: S2405-8033(20)30214-4. [Epub ahead of print]
    Raymundo DP, Doultsinos D, Guillory X, Carlesso A, Eriksson LA, Chevet E.
      IRE1α (inositol requiring enzyme 1 alpha) is one of the main transducers of the unfolded protein response (UPR). IRE1α plays instrumental protumoral roles in several cancers, and high IRE1α activity has been associated with poorer prognoses. In this context, IRE1α has been identified as a potentially relevant therapeutic target. Pharmacological inhibition of IRE1α activity can be achieved by targeting either the kinase domain or the RNase domain. Herein, the recent advances in IRE1α pharmacological targeting is summarized. We describe the identification and optimization of IRE1α inhibitors as well as their mode of action and limitations as anticancer drugs. The potential pitfalls and challenges that could be faced in the clinic, and the opportunities that IRE1α modulating strategies may present are discussed.
    Keywords:  IRE1; activators; endoplasmic reticulum; inhibitors; unfolded protein response
    DOI:  https://doi.org/10.1016/j.trecan.2020.07.006
  4. Mol Biol Cell. 2020 Sep 02. mbcE18010013
    Brown M, Dainty S, Strudwick N, Mihai AD, Watson JN, Dendooven R, Paton AW, Paton JC, Schröder M.
      Accumulation of unfolded proteins in the endoplasmic reticulum (ER) causes ER stress and activates a signalling network known as the unfolded protein response (UPR). Here we characterise how ER stress and the UPR inhibit insulin signalling. We find that ER stress inhibits insulin signalling by depleting the cell surface population of the insulin receptor. ER stress inhibits proteolytic maturation of insulin proreceptors by interfering with transport of newly synthesised insulin proreceptors from the ER to the plasma membrane. Activation of AKT, a major target of the insulin signalling pathway, by a cytosolic, membrane-bound chimera between the AP20187-inducible FV2E dimerisation domain and the cytosolic protein tyrosine kinase domain of the insulin receptor was not affected by ER stress. Hence, signalling events in the UPR, such as activation of the JNK MAP kinases or the pseudokinase TRB3 by the ER stress sensors IRE1α and PERK, do not contribute to inhibition of signal transduction in the insulin signalling pathway. Indeed, pharmacologic inhibition and genetic ablation of JNKs, as well as silencing of expression of TRB3, did not restore insulin sensitivity or rescue processing of newly synthesised insulin receptors in ER-stressed cells.
    DOI:  https://doi.org/10.1091/mbc.E18-01-0013
  5. Autophagy. 2020 Aug 31.
    Zhao D, Du LL.
      The endoplasmic reticulum (ER) is a major site of protein folding. Perturbations in the folding capacity of the ER result in ER stress. ER stress triggers autophagic degradation of the ER (reticulophagy). Molecular mechanisms underlying ER stress-induced reticulophagy remain largely unknown. Our recent study identified a soluble protein, Epr1, as an autophagy receptor for ER stress-induced reticulophagy in the fission yeast Schizosaccharomyces pombe. Epr1 can interact simultaneously with Atg8 and a VAP family integral ER membrane protein, and thereby act as a bridging molecule between them. VAP family proteins contribute to reticulophagy by not only connecting Atg8 to the ER membrane through Epr1, but also by supporting the ER-plasma membrane contact. The expression of Epr1 is upregulated during ER stress in a manner dependent on the unfolded protein response (UPR) regulator Ire1. Ire1 promotes reticulophagy by upregulating Epr1.
    Keywords:  ER stress; ER-phagy; ER-plasma membrane contact; Ire1; VAP; reticulophagy; selective autophagy; unfolded protein response (UPR)
    DOI:  https://doi.org/10.1080/15548627.2020.1816665
  6. Cell Death Dis. 2020 Sep 02. 11(8): 717
    Kim TW, Cheon C, Ko SG.
      In gastric cancer (GC), hypoxia is one of the greatest obstacles to cancer therapy. In this present study, we report that SH003, an herbal formulation, induces ER stress via PERK-ATF4-CHOP signaling in GC. SH003-mediated ER stress inhibits G9a, a histone methyltransferase, by reducing STAT3 phosphorylation and activates autophagy, indicating to the dissociation of Beclin-1 and autophagy initiation from Bcl-2/Beclin-1 complex. However, the inhibition of PERK and CHOP inhibited SH003-induced cell death and autophagy activation. Moreover, targeting autophagy using specific siRNAs of LC3B or p62 or the autophagy inhibitor 3-MA also inhibited SH003-induced cell death in GC. Interestingly, SH003 induces BNIP3-mediated autophagic cell death under hypoxia than normoxia in GC. These findings reveal that SH003-induced ER stress regulates BNIP3-induced autophagic cell death via inhibition of STAT3-G9a axis under hypoxia in GC. Therefore, SH003 may an important tumor therapeutic strategy under hypoxia-mediated chemo-resistance.
    DOI:  https://doi.org/10.1038/s41419-020-02924-w
  7. Cell Stress Chaperones. 2020 Sep 01.
    Li Z, Shen Y, Song Y, Zhang Y, Zhang C, Ma Y, Zhang F, Chen L.
      Endoplasmic reticulum stress (ER stress) can be induced by virus infection. In this part, we explored whether Hantaan virus (HTNV) infection could induce ER stress in differentiated THP-1 (dTHP-1) cells. It showed that the mRNA and protein levels of ER stress-related 78 kDa glucose-regulated protein (GRP78, HSPA5) and mRNA levels of X box-binding protein 1 (XBP-1), activating transcription factor 6(ATF6) and PKR-like ER kinase (PERK) after HTNV infection, were significantly higher than that in uninfected control group. However, the mRNA levels of C/EBP homologous protein (CHOP), glucose-regulated protein 94 (GRP94, HSPC4), and inositol-requiring enzyme1 (IRE1) were not significantly different between the infected group and the untreated group in 2 h after virus infection. It is unusual in activating GRP78 but not GRP94. Meanwhile, dTHP-1 cells infected with HTNV at 12 h did not show obvious apoptosis. These results indicated that the HTNV infection could induce the unfolded protein response (UPR) in dTHP-1 cells, without directly leading to cell apoptosis during 12 h after virus infection.
    Keywords:  78 kDa glucose-regulated protein (GRP78, HSPA5); Endoplasmic reticulum stress (ER stress); Hantaan virus (HTNV); Hemorrhagic fever with renal syndrome (HFRS); dTHP-1
    DOI:  https://doi.org/10.1007/s12192-020-01150-9
  8. Int J Mol Sci. 2020 Aug 31. pii: E6314. [Epub ahead of print]21(17):
    Yamashita Y, Morita S, Hosoi H, Kobata H, Kishimoto S, Ishibashi T, Mishima H, Kinoshita A, Backes BJ, Yoshiura KI, Papa FR, Sonoki T, Tamura S.
      BACKGROUND: Inositol-requiring enzyme 1α (IRE1α), along with protein kinase R-like endoplasmic reticulum kinase (PERK), is a principal regulator of the unfolded protein response (UPR). Recently, the 'mono'-specific IRE1α inhibitor, kinase-inhibiting RNase attenuator 6 (KIRA6), demonstrated a promising effect against multiple myeloma (MM). Side-stepping the clinical translation, a detailed UPR phenotype in patients with MM and the mechanisms of how KIRA8 works in MM remains unclear.METHODS: We characterized UPR phenotypes in the bone marrow of patients with newly diagnosed MM. Then, in human MM cells we analyzed the possible anti-tumor mechanisms of KIRA8 and a Food and Drug Administration (FDA)-approved drug, nilotinib, which we recently identified as having a strong inhibitory effect against IRE1α activity. Finally, we performed an RNA-sequence analysis to detect key IRE1α-related molecules against MM.
    RESULTS: We illustrated the dominant induction of adaptive UPR markers under IRE1α over the PERK pathway in patients with MM. In human MM cells, KIRA8 decreased cell viability and induced apoptosis, along with the induction of C/EBP homologous protein (CHOP); its combination with bortezomib exhibited more anti-myeloma effects than KIRA8 alone. Nilotinib exerted a similar effect compared with KIRA8. RNA-sequencing identified Polo-like kinase 2 (PLK2) as a KIRA8-suppressed gene. Specifically, the IRE1α overexpression induced PLK2 expression, which was decreased by KIRA8. KIRA8 and PLK2 inhibition exerted anti-myeloma effects with apoptosis induction and the regulation of cell proliferation. Finally, PLK2 was pathologically confirmed to be highly expressed in patients with MM.
    CONCLUSION: Dominant activation of adaptive IRE1α was established in patients with MM. Both KIRA8 and nilotinib exhibited anti-myeloma effects, which were enhanced by bortezomib. Adaptive IRE1α signaling and PLK2 could be potential therapeutic targets and biomarkers in MM.
    Keywords:  IRE1α; KIRA8; PLK2; multiple myeloma; nilotinib; unfolded protein response
    DOI:  https://doi.org/10.3390/ijms21176314
  9. J Clin Invest. 2020 Sep 01. pii: 139519. [Epub ahead of print]
    Katzen J, Beers MF.
      Epithelial cell dysfunction has emerged as a central component in the pathophysiology of diffuse parenchymal diseases including idiopathic pulmonary fibrosis (IPF). Alveolar type 2 (AT2) cells represent a metabolically active lung cell population important for surfactant biosynthesis and alveolar homeostasis. AT2 cells and other distal lung epithelia, like all eukaryotic cells, contain an elegant quality control (QC) network to respond to intrinsic metabolic and biosynthetic challenges imparted by mutant protein conformers, dysfunctional subcellular organelles, and dysregulated telomeres. Failed AT2 QC components (ubiquitin-proteasome system, unfolded protein response, macroautophagy, mitophagy, and telomere maintenance) result in diverse cellular endophenotypes and molecular signatures including ER stress, defective autophagy, mitochondrial dysfunction, apoptosis, inflammatory cell recruitment, profibrotic signaling, and altered progenitor function that ultimately converge to drive downstream fibrotic remodeling in the IPF lung. As this complex network becomes increasingly better understood, opportunities will emerge to identify targets and therapeutic strategies for IPF.
    DOI:  https://doi.org/10.1172/JCI139519
  10. Sci Rep. 2020 Sep 04. 10(1): 14159
    de Seny D, Bianchi E, Baiwir D, Cobraiville G, Collin C, Deliège M, Kaiser MJ, Mazzucchelli G, Hauzeur JP, Delvenne P, Malaise MG.
      It is now well recognized that osteoarthritis (OA) synovial membrane presents inflammatory components. The aim of this work is to provide evidence that similar inflammatory mechanisms exist in synovial membrane (n = 24) obtained from three pathologies presenting altogether an inflammatory gradient: OA, chronic pyrophosphate arthropathy (CPPA) and rheumatoid arthritis (RA). Synovial biopsies were first characterized by a histological score based on synovial hyperplasia and infiltration of lymphocytes, plasma cells, polymorphonuclear and macrophages. All biopsies were also analyzed by 2D-nano-UPLC-ESI-Q-Orbitrap for protein identification and quantification. Protein levels were correlated with the histological score. Histological score was in the range of 3 to 8 for OA, 5 to 13 for CPPA and 12 to 17 for RA. Of the 4,336 proteins identified by mass spectrometry, 51 proteins were selected for their strong correlation (p < 0.001) with the histological score of which 11 proteins (DNAJB11, CALR, ERP29, GANAB, HSP90B1, HSPA1A, HSPA5, HYOU1, LMAN1, PDIA4, and TXNDC5) were involved in the endoplasmic reticulum (ER) stress. Protein levels of S100A8 and S100A9 were significantly higher in RA compared to OA (for both) or to CPPA (for S100A8 only) and also significantly correlated with the histological score. Eighteen complement component proteins were identified, but only C1QB and C1QBP were weakly correlated with the histological score. This study highlights the inflammatory gradient existing between OA, CPPA and RA synovitis either at the protein level or at the histological level. Inflamed synovitis was characterized by the overexpression of ER stress proteins.
    DOI:  https://doi.org/10.1038/s41598-020-70803-7
  11. J Neurol. 2020 Sep 01.
    Santerre M, Arjona SP, Allen CN, Shcherbik N, Sawaya BE.
      SARS-CoV-2, which led to the 2020 global pandemic, is responsible for the Coronavirus Disease 2019 (COVID-19), a respiratory illness, and presents a tropism for the central nervous system. Like most members of this family, the virus is composed of structural and non-structural proteins (NSPs). The non-structural proteins are critical elements of the replication and transcription complex (RTC), as well as immune system evasion. Through hijacking the endoplasmic reticulum (ER) membrane, NSPs help the virus establish the RTC, inducing ER stress after membrane rearrangement and causing severe neuronal disturbance. In this review, we focus on the role of Nsp3, 4, and 6 in intracellular membrane rearrangement and evaluate the potential disruption of the central nervous system and the neurodegeneration which it could trigger. Studies of these NSPs will not only bring to light their specific role in viral infection but also facilitate the discovery of novel targeted drugs.
    Keywords:  COVID-19; Double-membrane vesicle; Endoplasmic reticulum stress; Golgi apparatus fragmentation; SARS-CoV-2
    DOI:  https://doi.org/10.1007/s00415-020-10197-8
  12. Diabetes Metab Syndr Obes. 2020 ;13 2843-2853
    Ramalingam L, Sopontammarak B, Menikdiwela KR, Moustaid-Moussa N.
      Introduction: The renin angiotensin aldosterone system (RAAS) is a hormone system known for its role in regulating blood pressure and fluid balance. Numerous RAAS inhibitors routinely prescribed for hypertension have also beneficial effects in type 2 diabetes (T2D) prevention. RAAS components are expressed locally in many tissues, including adipose tissue and pancreas, where they exert metabolic effects through RAAS bioactive hormone angiotensin II (Ang II). Pancreatic beta cells are specialized insulin-producing cells; they have also developed endoplasmic reticulum (ER), which contributes to beta cell dysfunction, when proteins are misfolded in disease states such as T2D. However, no studies have investigated the relationship between RAAS and ER stress in beta cells as a mechanism linking pancreatic RAAS to T2D. Hence, we hypothesized that Ang II treatment of beta cells increases ER stress and inflammation leading to reduced insulin secretion.Methods: To test this hypothesis, we treated clonal INS-1E beta cells and human islets with Ang II and assessed changes in ER stress markers. INS-1E beta cells were also used for measuring insulin secretion and for assessing the effects of various RAAS and ER stress inhibitors.
    Results: We demonstrated that Ang II significantly increased the expression of ER stress genes such as Chop and Atf4 and reduced insulin secretion. Furthermore, inhibition of Ang II production with an angiotensin converting enzyme inhibitor (ACEi, captopril) significantly reduced ER stress. Moreover, the Ang II receptor blockade reduced ER stress significantly and rescued insulin secretion.
    Discussion: This research provides new mechanistic insight into the role of RAAS activation via ER stress on beta cell dysfunction and provides additional evidence for protective effects of RAAS inhibition in T2D.
    Keywords:  ER stress; RAAS; beta cells; inflammation; renin angiotensin aldosterone system; type 2 diabetes
    DOI:  https://doi.org/10.2147/DMSO.S257797
  13. Cell Cycle. 2020 Aug 23. 1-11
    Song Q, He Z, Li B, Liu J, Liu L, Liao W, Xiong Y, Song C, Yang S, Liu Y.
      BACKGROUND: Deposition of various crystal and organic substances in the kidney can lead to kidney stone formation. Melatonin is an effective endogenous antioxidant that can prevent crystalluria and kidney damage due to crystal formation and aggregation. In this study, we investigated the mechanism by which melatonin inhibits endoplasmic reticulum (ER) stress and apoptosis.METHODS: We treated HK-2 cells with oxalate to establish an in vitro kidney stone model, and treated these cells with different concentrations of melatonin (0, 5, 10, 20 μmol/L) and the AMP-activated protein kinase (AMPK) inhibitor Compound C. We measured levels of stress response markers including reactive oxygen species (ROS), lactate dehydrogenase (LDH), glutathione (GSH), superoxide dismutase (SOD), malondialdehyde (MDA), catalase (CAT), and factors in the stress response pathway, such as ATF6, GRP78, DDIT3, PERK, p-PERK, IRE1, p-IRE1, XBP1s, AMPK, and p-AMPK, using real time-PCR, western blot, and immunofluorescence analyzes. We measured mitochondrial membrane potential and caspases-3 activity using the CCK8, enzyme-linked immunosorbent, and flow cytometry assays to assess HK-2 cell viability and apoptosis.
    RESULTS: Melatonin improved the total antioxidant capacity (T-AOC) of the HK-2 cells, as evidenced by the dose-dependent reduction in apoptosis, ROS levels, and protein expression of ATF6, GRP78, DDIT3, p-PERK, p-IRE1, XBP1s, caspase-12, cleaved caspase-3 and cleaved caspase-9. Addition of the AMPK inhibitor, Compound C, partially reversed the protective effect of melatonin.
    CONCLUSION: Our study revealed that the protective effects of melatonin on oxalate-induced ER stress and apoptosis is partly dependent on AMPK activation in HK-2 cells. These findings provide insight into the prevention and treatment of kidney stones.
    Keywords:  AMPK; Kidney stone; apoptosis; endoplasmic reticulum stress; melatonin; oxalate
    DOI:  https://doi.org/10.1080/15384101.2020.1810401
  14. J Clin Invest. 2020 Aug 31. pii: 140793. [Epub ahead of print]
    Wu T, Chen J.
      The right ventricle (RV) is involved in systemic circulation in the fetal mammalian heart but quickly transitions to being solely responsible for pulmonary circulation after birth when the left ventricle (LV) becomes the systemic ventricle. To handle the increased workload, LV growth greatly outpaces that of the RV during postnatal stages. However, the molecular basis for this differential growth pattern between the 2 chambers is largely unknown. In this issue of the JCI, Yokota et al. reveal that the p38 mitogen-activated protein kinase (MAPK)/IRE1α/XBP1 axis specifically controls postnatal RV growth by suppressing cell cycle regulatory genes.
    DOI:  https://doi.org/10.1172/JCI140793