bims-unfpre Biomed News
on Unfolded protein response
Issue of 2021‒03‒14
eleven papers selected by
Susan Logue
University of Manitoba

  1. Biochim Biophys Acta Mol Cell Res. 2021 Mar 08. pii: S0167-4889(21)00055-0. [Epub ahead of print] 119001
      Endoplasmic Reticulum (ER) stress signaling is an adaptive mechanism triggered when protein folding demand overcomes the folding capacity of this compartment, thereby leading to the accumulation of improperly folded proteins. This stress signaling pathway is named the Unfolded Protein Response (UPR) and aims at restoring ER homeostasis. However, if this fails, mechanisms orienting cells towards death processes are initiated. Herein, we summarize the most recent findings connecting ER stress and the UPR with identified death mechanisms including apoptosis, necrosis, pyroptosis, ferroptosis, and autophagy. We highlight new avenues that could be investigated and controlled through actionable mechanisms in physiology and pathology.
    Keywords:  Apoptosis; Autophagy; Cell death; Endoplasmic reticulum; Ferroptosis; Pyroptosis; Unfolded protein response
  2. EMBO Rep. 2021 Mar 12. e51412
      In the past decades, many studies reported the presence of endoplasmic reticulum (ER)-resident proteins in the cytosol. However, the mechanisms by which these proteins relocate and whether they exert cytosolic functions remain unknown. We find that a subset of ER luminal proteins accumulates in the cytosol of glioblastoma cells isolated from mouse and human tumors. In cultured cells, ER protein reflux to the cytosol occurs upon ER proteostasis perturbation. Using the ER luminal protein anterior gradient 2 (AGR2) as a proof of concept, we tested whether the refluxed proteins gain new functions in the cytosol. We find that refluxed, cytosolic AGR2 binds and inhibits the tumor suppressor p53. These data suggest that ER reflux constitutes an ER surveillance mechanism to relieve the ER from its contents upon stress, providing a selective advantage to tumor cells through gain-of-cytosolic functions-a phenomenon we name ER to Cytosol Signaling (ERCYS).
    Keywords:  ER stress; ERAD; cancer; endoplasmic reticulum; reflux
  3. Trends Cell Biol. 2021 Mar 05. pii: S0962-8924(21)00029-5. [Epub ahead of print]
      The biosynthesis of about one third of the human proteome, including membrane receptors and secreted proteins, occurs in the endoplasmic reticulum (ER). Conditions that perturb ER homeostasis activate the unfolded protein response (UPR). An 'optimistic' UPR output aims at restoring homeostasis by reinforcement of machineries that guarantee efficiency and fidelity of protein biogenesis in the ER. Yet, once the UPR 'deems' that ER homeostatic readjustment fails, it transitions to a 'pessimistic' output, which, depending on the cell type, will result in apoptosis. In this article, we discuss emerging concepts on how the UPR 'evaluates' ER stress, how the UPR is repurposed, in particular in B cells, and how UPR-driven counter-selection of cells undergoing homeostatic failure serves organismal homeostasis and humoral immunity.
    Keywords:  B cell development; RIDD; antibody production; endoplasmic reticulum; proteostasis; unfolded protein response
  4. Cancer Sci. 2021 Mar 09.
      The unfolded protein response (UPR) plays an important role in carcinogenesis, but the functional role and mechanism of UPR-associated bladder carcinogenesis remain to be characterized. Upon UPR activation, ATF6α is activated to upregulate the transcription of UPR target genes. Although the mechanism of ATF6 activation has been studied extensively, the negative regulation of ATF6 stabilization is not well understood. Here, we report that the deubiquitinase otubain 1 (OTUB1) facilitates bladder cancer progression by stabilizing ATF6 in response to ER stress. OTUB1 expression is elevated in bladder cancer patients. Genetic ablation of OTUB1 markedly inhibited bladder cancer cell proliferation, viability and migration both in vitro and in vivo. Mechanistically, luciferase pathway screening showed that ATF6 signaling was clearly activated compared to other pathways. OTUB1 was found to activate ATF6 signaling by inhibiting its ubiquitylation, thereby remodeling the stressed cells through transcriptional regulation. Our results indicate that high OTUB1 expression promotes bladder cancer progression by stabilizing ATF6 and that OTUB1 is a potential therapeutic target in bladder cancer.
    Keywords:  ATF6; OTUB1; UPR; bladder cancer; deubiquitination
  5. Endocr Rev. 2021 Mar 08. pii: bnab006. [Epub ahead of print]
      The endoplasmic reticulum (ER) hosts linear polypeptides and fosters natural folding of proteins through ER-residing chaperones and enzymes. Failure of the ER to align and compose proper protein architecture leads to accumulation of misfolded/unfolded proteins in the ER lumen, which disturbs ER homeostasis to provoke ER stress. Presence of ER stress initiates the cytoprotective unfolded protein response (UPR) to restore ER homeostasis or instigates a rather maladaptive UPR to promote cell death. Although a wide array of cellular processes such as persistent autophagy, dysregulated mitophagy, and secretion of pro-inflammatory cytokines may contribute to the onset and progression of cardiometabolic diseases, it is well perceived that ER stress also evokes onset and development of cardiometabolic diseases, particularly, cardiovascular diseases, diabetes mellitus, obesity, and chronic kidney disease. Meanwhile, these pathological conditions further aggravate ER stress, creating a rather vicious cycle. Here in this review, we aimed at summarizing and updating the available information on ER stress in cardiovascular diseases, diabetes mellitus, obesity, and chronic kidney disease, hoping to offer novel insights for the management of these cardiometabolic comorbidities through regulation of ER stress.
    Keywords:  ER stress; cardiometabolic disease; chronic kidney disease; diabetes; obesity
  6. Methods Mol Biol. 2021 Mar 11.
      The reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) has proven to be a powerful system creating new opportunities to interrogate molecular mechanisms controlling cell fate determination. Under standard conditions, the generation of iPSCs upon overexpression of OCT4, SOX2, KLF4, and c-MYC (OSKM) is generally slow and inefficient due to the presence of barriers that confer resistance to cell fate changes. Hyperactivated endoplasmic reticulum (ER) stress has emerged as a major reprogramming barrier that impedes the initial mesenchymal-to-epithelial transition (MET) step to form iPSCs from mesenchymal somatic cells. Here, we describe several systems to detect ER stress in the context of OSKM reprogramming and chemical interventions to modulate this process for improving iPSC formation.
    Keywords:  Cell fate change; Endoplasmic reticulum stress; Induced pluripotent stem cell; Mesenchymal-to-epithelial transition; Pluripotency; Unfolded protein response
  7. Neuron. 2021 Mar 04. pii: S0896-6273(21)00123-9. [Epub ahead of print]
      Store-operated calcium entry (SOCE) is activated by depletion of Ca2+ from the endoplasmic reticulum (ER) and mediated by stromal interaction molecule (STIM) proteins. Here, we show that in rat and mouse hippocampal neurons, acute ER Ca2+ depletion increases presynaptic Ca2+ levels and glutamate release through a pathway dependent on STIM2 and the synaptic Ca2+ sensor synaptotagmin-7 (syt7). In contrast, synaptotagmin-1 (syt1) can suppress SOCE-mediated spontaneous release, and STIM2 is required for the increase in spontaneous release seen during syt1 loss of function. We also demonstrate that chronic ER stress activates the same pathway leading to syt7-dependent potentiation of spontaneous glutamate release. During ER stress, inhibition of SOCE or syt7-driven fusion partially restored basal neurotransmission and decreased expression of pro-apoptotic markers, indicating that these processes participate in the amplification of ER-stress-related damage. Taken together, we propose that presynaptic SOCE links ER stress and augmented spontaneous neurotransmission, which may, in turn, facilitate neurodegeneration.
    Keywords:  Orai; STIM2; calcium; endoplasmic reticulum stress; spontaneous neurotrasnmission; store operated calcium entry; synaptic vesicle; synaptotagmin-7
  8. Front Immunol. 2021 ;12 604974
      Antigen (Ag)-mediated mast cell activation plays a critical role in the immunopathology of IgE-dependent allergic diseases. Restraining the signaling cascade that regulates the release of mast cell-derived inflammatory mediators is an attractive therapeutic strategy to treat allergic diseases. Orosomucoid-like-3 (ORMDL3) regulates the endoplasmic reticulum stress (ERS)-induced unfolded protein response (UPR) and autophagy. Although ERS/UPR/autophagy pathway is crucial in Ag-induced mast cell activation, it is unknown whether ORMDL3 regulates the ERS/UPR/autophagy pathway during mast cell activation. In this study, we found that ORMDL3 expression was downregulated in Ag-activated MC/9 cells. Overexpression of ORMDL3 significantly inhibited degranulation, and cytokine/chemokine production, while the opposite effect was observed with ORMDL3 knockdown in MC/9 cells. Importantly, ORMDL3 overexpression upregulated mediators of ERS-UPR (SERCA2b, ATF6) and autophagy (Beclin 1 and LC3BII). Knockdown of ATF6 and/or inhibition of autophagy reversed the decreased degranulation and cytokine/chemokine expression caused by ORMDL3 overexpression. Moreover, in vivo knockdown of ORMDL3 and/or ATF6 enhanced passive cutaneous anaphylaxis (PCA) reactions in mouse ears. These data indicate that ORMDL3 suppresses Ag-mediated mast cell activation via an ATF6 UPR-autophagy dependent pathway and thus, attenuates anaphylactic reaction. This highlights a potential mechanism to intervene in mast cell mediated diseases.
    Keywords:  activating transcription factor 6; autophagy; degranulation; mast cell activation; orosomucoid-like 3; passive cutaneous anaphylaxis
  9. Immunohorizons. 2021 Mar 08. 5(3): 135-146
      The ability to modulate direct MHC class I (MHC I) Ag presentation is a desirable goal for the treatment of a variety of conditions, including autoimmune diseases, chronic viral infections, and cancers. It is therefore necessary to understand how changes in the cellular environment alter the cells' ability to present peptides to T cells. The unfolded protein response (UPR) is a signaling pathway activated by the presence of excess unfolded proteins in the endoplasmic reticulum. Previous studies have indicated that chemical induction of the UPR decreases direct MHC I Ag presentation, but the precise mechanisms are unknown. In this study, we used a variety of small molecule modulators of different UPR signaling pathways to query which UPR signaling pathways can alter Ag presentation in both murine and human cells. When signaling through the PERK pathway, and subsequent eIF2α phosphorylation, was blocked by treatment with GSK2656157, MHC I Ag presentation remain unchanged, whereas treatment with salubrinal, which has the opposite effect of GSK2656157, decreases both Ag presentation and overall cell-surface MHC I levels. Treatment with 4μ8C, an inhibitor of the IRE1α UPR activation pathway that blocks splicing of Xbp1 mRNA, also diminished MHC I Ag presentation. However, 4μ8C treatment unexpectedly led to an increase in eIF2α phosphorylation in addition to blocking IRE1α signaling. Given that salubrinal and 4μ8C lead to eIF2α phosphorylation and similar decreases in Ag presentation, we conclude that UPR signaling through PERK, leading to eIF2α phosphorylation, results in a modest decrease in direct MHC I Ag presentation.
  10. BMC Cancer. 2021 Mar 06. 21(1): 237
      BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC), one of the most lethal cancers, is driven by oncogenic KRAS mutations. Farnesyl thiosalicylic acid (FTS), also known as salirasib, is a RAS inhibitor that selectively dislodges active RAS proteins from cell membrane, inhibiting downstream signaling. FTS has demonstrated limited therapeutic efficacy in PDAC patients despite being well tolerated.METHODS: To improve the efficacy of FTS in PDAC, we performed a genome-wide CRISPR synthetic lethality screen to identify genetic targets that synergize with FTS treatment. Among the top candidates, multiple genes in the endoplasmic reticulum-associated protein degradation (ERAD) pathway were identified. The role of ERAD inhibition in enhancing the therapeutic efficacy of FTS was further investigated in pancreatic cancer cells using pharmaceutical and genetic approaches.
    RESULTS: In murine and human PDAC cells, FTS induced unfolded protein response (UPR), which was further augmented upon treatment with a chemical inhibitor of ERAD, Eeyarestatin I (EerI). Combined treatment with FTS and EerI significantly upregulated the expression of UPR marker genes and induced apoptosis in pancreatic cancer cells. Furthermore, CRISPR-based genetic ablation of the key ERAD components, HRD1 and SEL1L, sensitized PDAC cells to FTS treatment.
    CONCLUSION: Our study reveals a critical role for ERAD in therapeutic response of FTS and points to the modulation of UPR as a novel approach to improve the efficacy of FTS in PDAC treatment.
    Keywords:  Clusters of regularly interspaced short palindromic repeats (CRISPR); Endoplasmic reticulum-associated protein degradation (ERAD); Farnesyl thiosalicylic acid (FTS); Pancreatic ductal adenocarcinoma (PDAC); Salirasib; Unfolded protein response (UPR)
  11. Aging Brain. 2021 ;pii: 100009. [Epub ahead of print]1
      Blood brain barrier hyperpermeability has been associated with age-related affective disorders, including depression, mania, anxiety, Alzheimer's and Parkinson's disease. Our recent efforts suggest that a promising therapeutic approach may arise due to the activation of the unfolded protein response (UPR) element in the affected tissues. Growth hormone releasing hormone antagonists and heat shock protein 90 inhibitors have been shown to induce UPR. This mechanism (UPR) has been associated with tissue repairing processes.
    Keywords:  Blood brain barrier; Growth hormone releasing hormone; P53; Reactive oxygen species; Unfolded protein response