bims-unfpre Biomed News
on Unfolded protein response
Issue of 2021‒02‒14
thirteen papers selected by
Susan Logue
University of Manitoba

  1. Biomedicines. 2021 Feb 05. pii: 156. [Epub ahead of print]9(2):
      Inositol-requiring enzyme type 1 (IRE1) is a serine/threonine kinase acting as one of three branches of the Unfolded Protein Response (UPR) signaling pathway, which is activated upon endoplasmic reticulum (ER) stress conditions. It is known to be capable of inducing both pro-survival and pro-apoptotic cellular responses, which are strictly related to numerous human pathologies. Among others, IRE1 activity has been confirmed to be increased in cancer, neurodegeneration, inflammatory and metabolic disorders, which are associated with an accumulation of misfolded proteins within ER lumen and the resulting ER stress conditions. Emerging evidence suggests that genetic or pharmacological modulation of IRE1 may have a significant impact on cell viability, and thus may be a promising step forward towards development of novel therapeutic strategies. In this review, we extensively describe the structural analysis of IRE1 molecule, the molecular dynamics associated with IRE1 activation, and interconnection between it and the other branches of the UPR with regard to its potential use as a therapeutic target. Detailed knowledge of the molecular characteristics of the IRE1 protein and its activation may allow the design of specific kinase or RNase modulators that may act as drug candidates.
    Keywords:  Regulated IRE1-Dependent Decay (RIDD); Unfolded Protein Response (UPR); apoptosis; c-Jun N-terminal kinase (JNK); drug development; endoplasmic reticulum (ER) stress; factor X-box binding protein 1 (XBP1); inositol-requiring enzyme type 1 (IRE1)
  2. J Clin Invest. 2021 Feb 09. pii: 137866. [Epub ahead of print]
      Neutrophils amplify inflammation in lupus through release of neutrophil extracellular traps (NETs). The endoplasmic reticulum stress sensor inositol-requiring enzyme 1 alpha (IRE1α) has been implicated as a perpetuator of inflammation in various chronic diseases; however, IRE1α has been little studied in relation to neutrophil function or lupus pathogenesis. Here, we found that neutrophils activated by lupus-derived immune complexes demonstrate markedly increased IRE1α ribonuclease activity. Importantly, heightened IRE1α activity was also detected in neutrophils isolated from lupus patients, where it correlated with global disease activity. Immune complex-stimulated neutrophils produced both mitochondrial reactive oxygen species (mitoROS) and the activated form of caspase-2 in IRE1α-dependent fashion, while inhibition of IRE1α mitigated immune complex-mediated NETosis (both in human neutrophils and in a mouse model of lupus). Administration of an IRE1α inhibitor to lupus-prone MRL/lpr mice over eight weeks reduced mitochondrial ROS levels in peripheral blood neutrophils, while also restraining plasma-cell expansion and autoantibody formation. In summary, these data are the first to identify a role for IRE1α in the hyperactivity of lupus neutrophils, with this pathway apparently upstream of mitochondrial dysfunction, mitochondrial ROS formation, and NETosis. Inhibition of the IRE1α pathway appears to be a novel strategy for neutralizing NETosis in lupus, and potentially other inflammatory conditions.
    Keywords:  Autoimmunity; Cell stress; Immunology; Lupus; Neutrophils
  3. J Cell Physiol. 2021 Feb 12.
      AAA domain containing 3A (ATAD3A) is a nucleus-encoded mitochondrial protein with vital function in communication between endoplasmic reticulum (ER) and mitochondria which is participated in cancer metastasis. Here we show that elevated ATAD3A expression is clinically associated with poor 5-year disease-free survival in patients with colorectal cancer (CRC), especially high-risk CRC patients who received adjuvant chemotherapy. Our results indicated ATAD3A is significantly upregulated to reduce chemotherapy-induced cancer cell death. We found that knockdown of ATAD3A leads to dysregulation in protein processing for inducing ER stress by RNA sequencing (RNA-seq). In response to chemotherapy-induced ER stress, ATAD3A interacts with elevated GRP78 protein to assist protein folding and alleviate ER stress for cancer cell survival. This reduction of ER stress leads to reduce the surface exposure of calreticulin, which is the initiator of immunogenic cell death and antitumor immunity. However, silencing of ATAD3A enhances cell death, triggers the feasibility of chemotherapy-induced ER stress for antitumor immunity, increases infiltration of T lymphocytes and delays tumor regrowth in vitro and in vivo. Clinically, CRC patients with less ATAD3A have high density of CD45+ intratumoral infiltrating lymphocytes (TILs) and memory CD45RO+ TILs. Taken together, our results suggest that pharmacologic targeting to ATAD3A might be a potential therapeutic strategy to enhance antitumor immunity for CRC patients who received adjuvant chemotherapy.
    Keywords:  ATPase family AAA domain containing 3A (ATAD3A); ER stress; colon carcinoma; glucose-regulated protein 78 kDa (GRP78); immunogenic cell death
  4. Biomolecules. 2021 Jan 30. pii: 199. [Epub ahead of print]11(2):
      The unfolded protein response (UPR) is an evolutionarily conserved adaptive signaling pathway triggered by a stress of the endoplasmic reticulum (ER) lumen compartment, which is initiated by the accumulation of unfolded proteins. This response, mediated by three sensors-Inositol Requiring Enzyme 1 (IRE1), Activating Transcription Factor 6 (ATF6), and Protein Kinase RNA-Like Endoplasmic Reticulum Kinase (PERK)-allows restoring protein homeostasis and maintaining cell survival. UPR represents a major cytoprotective signaling network for cancer cells, which frequently experience disturbed proteostasis owing to their rapid proliferation in an usually unfavorable microenvironment. Increased basal UPR also participates in the resistance of tumor cells against chemotherapy. UPR activation also occurs during hematopoiesis, and growing evidence supports the critical cytoprotective role played by ER stress in the emergence and proliferation of leukemic cells. In case of severe or prolonged stress, pro-survival UPR may however evolve into a cell death program called terminal UPR. Interestingly, a large number of studies have revealed that the induction of proapoptotic UPR can also strongly contribute to the sensitization of leukemic cells to chemotherapy. Here, we review the current knowledge on the consequences of the deregulation of UPR signaling in leukemias and their implications for the treatment of these diseases.
    Keywords:  ALL; AML; CLL; CML; endoplasmic reticulum stress; leukemia; unfolded protein response (UPR)
  5. Cell Death Discov. 2020 Feb 18. 6(1): 8
      Genetic obesity increases in liver phosphatidylcholine (PC)/phosphatidylethanolamine (PE) ratio, inducing endoplasmic reticulum (ER) stress without concomitant increase of ER chaperones. Here, it is found that exposing mice to a palm oil-based high fat (HF) diet induced obesity, loss of liver PE, and loss of the ER chaperone Grp78/BiP in pericentral hepatocytes. In Hepa1-6 cells treated with elevated concentration of palmitate to model lipid stress, Grp78/BiP mRNA was increased, indicating onset of stress-induced Unfolded Protein Response (UPR), but Grp78/BiP protein abundance was nevertheless decreased. Exposure to elevated palmitate also induced in hepatoma cells decreased membrane glycosylation, nuclear translocation of pro-apoptotic C/EBP-homologous-protein-10 (CHOP), expansion of ER-derived quality control compartment (ERQC), loss of mitochondrial membrane potential (MMP), and decreased oxidative phosphorylation. When PE was delivered to Hepa1-6 cells exposed to elevated palmitate, effects by elevated palmitate to decrease Grp78/BiP protein abundance and suppress membrane glycosylation were blunted. Delivery of PE to Hepa1-6 cells treated with elevated palmitate also blunted expansion of ERQC, decreased nuclear translocation of CHOP and lowered abundance of reactive oxygen species (ROS). Instead, delivery of the chemical chaperone 4-phenyl-butyrate (PBA) to Hepa1-6 cells treated with elevated palmitate, while increasing abundance of Grp78/BiP protein and restoring membrane glycosylation, also increased ERQC, expression and nuclear translocation of CHOP, non-mitochondrial oxygen consumption, and generation of ROS. Data indicate that delivery of PE to hepatoma cells under lipid stress recovers cell function by targeting the secretory pathway and by blunting pro-apoptotic branches of the UPR.
  6. Cancer Lett. 2021 Feb 05. pii: S0304-3835(21)00014-8. [Epub ahead of print]
      Despite technological advances in cancer treatment, the survival rate of patients with head and neck cancer (HNC) has not improved significantly. Many studies have shown that endoplasmic reticulum (ER) stress-related signals are associated with mitochondrial damage and that these signals determine whether cells maintain homeostasis or activate cell death programs. The unfolded protein response (UPR) is regulated by ER membrane proteins such as double-stranded RNA-activated protein kinase R(PKR)-like ER kinase (PERK), which directly activate transcription of chaperones or genes that function in redox homeostasis, protein secretion, or cell death programs. In this study, we focused on the role of mitophagy and ER stress-mediated cell death induced by DIM-C-pPhtBu in HNC cancer. We found that DIM-C-pPhtBu, a compound that activates ER stress in many cancers, induced lysosomal dysfunction, excessive mitophagy, and cell death in HNC cells. Moreover, DIM-C-pPhtBu strongly inhibited HNC progression in a xenograft model by altering mitophagy related protein expression. Taken together, the results demonstrate that DIM-C-pPhtBu induces excessive mitophagy and eventually UPR-mediated cell death in HNC cells, suggesting that new anti-cancer drugs could be developed based on the connection between mitophagy and cancer cell death.
    Keywords:  3,3′-diindolylmethane (DIM); Apoptosis-linked gene 2-interacting protein X (AIP1/Alix); Differentially expressed genes (DEGs); Double-stranded RNA-Activated protein kinase-like ER kinase (PERK); Endoplasmic reticulum stress; HNC (Head and neck cancer)
  7. Front Immunol. 2020 ;11 611347
      The anti-viral pattern recognition receptor STING and its partnering cytosolic DNA sensor cGAS have been increasingly recognized to respond to self DNA in multiple pathologic settings including cancer and autoimmune disease. Endogenous DNA sources that trigger STING include damaged nuclear DNA in micronuclei and mitochondrial DNA (mtDNA). STING resides in the endoplasmic reticulum (ER), and particularly in the ER-mitochondria associated membranes. This unique location renders STING well poised to respond to intracellular organelle stress. Whereas the pathways linking mtDNA and STING have been addressed recently, the mechanisms governing ER stress and STING interaction remain more opaque. The ER and mitochondria share a close anatomic and functional relationship, with mutual production of, and inter-organelle communication via calcium and reactive oxygen species (ROS). This interdependent relationship has potential to both generate the essential ligands for STING activation and to regulate its activity. Herein, we review the interactions between STING and mitochondria, STING and ER, ER and mitochondria (vis-à-vis calcium and ROS), and the evidence for 3-way communication.
    Keywords:  STING; cGAS; endoplasmic reticulum; mitochondria; reactive oxygen species; unfolded protein response
  8. Cell Death Discov. 2020 Apr 17. 6(1): 22
      To address unmet clinical need for uveal melanomas, we assessed the effects of BH3-mimetic molecules, the ABT family, known to exert pro-apoptotic activities in cancer cells. Our results uncovered that ABT-263 (Navitoclax), a potent and orally bioavailable BCL-2 family inhibitor, induced antiproliferative effects in metastatic human uveal melanoma cells through cell cycle arrest at the G0/G1 phase, loss of mitochondrial membrane potential, and subsequently apoptotic cell death monitored by caspase activation and poly-ADP ribose polymerase cleavage. ABT-263-mediated reduction in tumor growth was also observed in vivo. We observed in some cells that ABT-263 treatment mounted a pro-survival response through activation of the ER stress signaling pathway. Blocking the PERK signaling pathway increased the pro-apoptotic ABT-263 effect. We thus uncovered a resistance mechanism in uveal melanoma cells mediated by activation of endoplasmic reticulum stress pathway. Therefore, our study identifies ABT-263 as a valid therapeutic option for patients suffering from uveal melanoma.
  9. Exp Mol Med. 2021 Feb 08.
      The endoplasmic reticulum (ER) is an essential organelle of eukaryotic cells. Its main functions include protein synthesis, proper protein folding, protein modification, and the transportation of synthesized proteins. Any perturbations in ER function, such as increased demand for protein folding or the accumulation of unfolded or misfolded proteins in the ER lumen, lead to a stress response called the unfolded protein response (UPR). The primary aim of the UPR is to restore cellular homeostasis; however, it triggers apoptotic signaling during prolonged stress. The core mechanisms of the ER stress response, the failure to respond to cellular stress, and the final fate of the cell are not yet clear. Here, we discuss cellular fate during ER stress, cross talk between the ER and mitochondria and its significance, and conditions that can trigger ER stress response failure. We also describe how the redox environment affects the ER stress response, and vice versa, and the aftermath of the ER stress response, integrating a discussion on redox imbalance-induced ER stress response failure progressing to cell death and dynamic pathophysiological changes.
  10. J Hepatol. 2021 Feb 03. pii: S0168-8278(21)00090-8. [Epub ahead of print]
      BACKGROUND & AIMS: Chronic ER stress in liver have been shown to play a causative role in NAFLD progression, yet the underlying molecular mechanisms remain to be elucidated. Forkhead box A3 (FOXA3), a members of FOX family, plays critical roles in metabolic homeostasis, while its possible functions in ER stress and fatty liver progression are unknown.METHODS: FOXA3 gain- and loss-of-function animal models were achieved via adenoviral delivery, siRNA delivery or genetic knockout mice. Tunicamycin (TM) and high-fat-diet (HFD) were administrated in mice to induce acute or chronic ER stress. ChIP-seq, luciferase assay and adenoviral-mediated downstream gene manipulations were performed to reveal the transcriptional axis involved. Key axis protein levels in livers from healthy donors and NAFLD patients were assessed via immunohistochemical staining.
    RESULTS: FOXA3 transcription is specifically induced by XBP1s upon ER stress. FOXA3 exacerbates the excessive lipid accumulation caused by acute ER-inducer TM, while FOXA3 deficiency in hepatocytes and mice alleviates it. Importantly, FOXA3 deficiency in mice reduced diet-induced chronic ER stress, fatty liver and insulin resistance. In addition, FOXA3 suppression via siRNA or AAV delivery treated fatty liver phenotype in HFD-induced obese mice and in db/db mice. Mechanistically, ChIP-Seq analysis revealed that FOXA3 directly regulates Period1 (Per1) transcription, which in turn promotes the expression of lipogenic genes including Srebp1c to enhance lipid synthesis. Of pathophysiological significance, FOXA3, PER1 and SREBP1c levels were increased in livers of obese mice and NAFLD patients.
    CONCLUSION: The present study identified FOXA3 as the bridging molecule that links ER stress and NAFLD progression. Our results highlighted the XBP1s-FOXA3-PER1/Srebp1c transcriptional axis in the development of NAFLD and provided FOXA3 as a potential therapeutic target for fatty liver disease.
    Keywords:  ER stress; Hepatic steatosis; Lipogenesis; Non-alcoholic fatty liver disease; Triglyceride
  11. Aging Cell. 2021 Feb 09. e13319
      As they age, adult stem cells become more prone to functional decline, which is responsible for aging-associated tissue degeneration and diseases. One goal of aging research is to identify drugs that can repair age-associated tissue degeneration. Multiple organ development-related signaling pathways have recently been demonstrated to have functions in tissue homeostasis and aging process. Therefore, in this study, we tested several chemicals that are essential for organ development to assess their ability to delay intestinal stem cell (ISC) aging and promote gut function in adult Drosophila. We found that taurine, a free amino acid that supports neurological development and tissue metabolism in humans, represses ISC hyperproliferation and restrains the intestinal functional decline seen in aged animals. We found that taurine represses age-associated ISC hyperproliferation through a mechanism that eliminated endoplasmic reticulum (ER) stress by upregulation of the target genes of unfolded protein response in the ER (UPRER ) and inhibiting the c-Jun N-terminal kinase (JNK) signaling. Our findings show that taurine plays a critical role in delaying the aging process in stem cells and suggest that it may be used as a natural compound for the treatment of age-associated, or damage-induced intestinal dysfunction in humans.
    Keywords:  ER stress; JNK signaling; aging; gut; intestinal stem cell; taurine; unfolded protein response
  12. FASEB J. 2021 Mar;35(3): e21395
      Non-alcoholic fatty liver (NAFL) and related syndromes affect one-third of the adult population in industrialized and developing countries. Lifestyle and caloric oversupply are the main causes of such array of disorders, but the molecular mechanisms underlying their etiology remain elusive. Nuclear Protein 1 (NUPR1) expression increases upon cell injury in all organs including liver. Recently, we reported NUPR1 actively participates in the activation of the Unfolded Protein Response (UPR). The UPR typically maintains protein homeostasis, but downstream mediators of the pathway regulate metabolic functions including lipid metabolism. As increases in UPR and NUPR1 in obesity and liver disease have been well documented, the goal of this study was to investigate the roles of NUPR1 in this context. To establish whether NUPR1 is involved in these liver conditions we used patient-derived liver biopsies and in vitro and in vivo NUPR1 loss of functions models. First, we analyzed NUPR1 expression in a cohort of morbidly obese patients (MOPs), with simple fatty liver (NAFL) or more severe steatohepatitis (NASH). Next, we explored the metabolic roles of NUPR1 in wild-type (Nupr1+/+ ) or Nupr1 knockout mice (Nupr1-/- ) fed with a high-fat diet (HFD) for 15 weeks. Immunohistochemical and mRNA analysis revealed NUPR1 expression is inversely correlated to hepatic steatosis progression. Mechanistically, we found NUPR1 participates in the activation of PPAR-α signaling via UPR. As PPAR-α signaling is controlled by UPR, collectively, these findings suggest a novel function for NUPR1 in protecting liver from metabolic distress by controlling lipid homeostasis, possibly through the UPR.
    Keywords:  NAFL; NASH; NUPR1; PPAR-a signalling; UPR; lipotoxicity
  13. Int J Mol Sci. 2021 Jan 25. pii: 1156. [Epub ahead of print]22(3):
      In addition to their classical roles as bacterial sensors, NOD1 and NOD2 have been implicated as mediators of metabolic disease. Increased expression of NOD1 and/or NOD2 has been reported in a range of human metabolic diseases, including obesity, diabetes, non-alcoholic fatty liver disease, and metabolic syndrome. Although NOD1 and NOD2 share intracellular signaling pathway components, they are differentially upregulated on a cellular level and have opposing impacts on metabolic disease development in mouse models. These NOD-like receptors may directly mediate signaling downstream of cell stressors, such as endoplasmic reticulum stress and calcium influx, or in response to metabolic signals, such as fatty acids and glucose. Other studies suggest that stimulation of NOD1 or NOD2 by their bacterial ligands can result in inflammation, altered insulin responses, increased reactive oxygen signaling, and mitochondrial dysfunction. The activating stimuli for NOD1 and NOD2 in the context of metabolic disease are controversial and may be a combination of both metabolic and circulating bacterial ligands. In this review, we will summarize the current knowledge of how NOD1 and NOD2 may mediate metabolism in health and disease, as well as highlight areas of future investigation.
    Keywords:  ER stress; NLR; diabetes; high fat diet; hypoxia; insulin resistance; metabolic syndrome; metabolism; mitochondria; obesity