bims-unfpre Biomed News
on Unfolded protein response
Issue of 2019‒05‒05
eleven papers selected by
Susan Logue
University of Manitoba


  1. EMBO Mol Med. 2019 Apr 30. pii: e10120. [Epub ahead of print]
    Maurel M, Obacz J, Avril T, Ding YP, Papadodima O, Treton X, Daniel F, Pilalis E, Hörberg J, Hou W, Beauchamp MC, Tourneur-Marsille J, Cazals-Hatem D, Sommerova L, Samali A, Tavernier J, Hrstka R, Dupont A, Fessart D, Delom F, Fernandez-Zapico ME, Jansen G, Eriksson LA, Thomas DY, Jerome-Majewska L, Hupp T, Chatziioannou A, Chevet E, Ogier-Denis E.
      Anterior gradient 2 (AGR2) is a dimeric protein disulfide isomerase family member involved in the regulation of protein quality control in the endoplasmic reticulum (ER). Mouse AGR2 deletion increases intestinal inflammation and promotes the development of inflammatory bowel disease (IBD). Although these biological effects are well established, the underlying molecular mechanisms of AGR2 function toward inflammation remain poorly defined. Here, using a protein-protein interaction screen to identify cellular regulators of AGR2 dimerization, we unveiled specific enhancers, including TMED2, and inhibitors of AGR2 dimerization, that control AGR2 functions. We demonstrate that modulation of AGR2 dimer formation, whether enhancing or inhibiting the process, yields pro-inflammatory phenotypes, through either autophagy-dependent processes or secretion of AGR2, respectively. We also demonstrate that in IBD and specifically in Crohn's disease, the levels of AGR2 dimerization modulators are selectively deregulated, and this correlates with severity of disease. Our study demonstrates that AGR2 dimers act as sensors of ER homeostasis which are disrupted upon ER stress and promote the secretion of AGR2 monomers. The latter might represent systemic alarm signals for pro-inflammatory responses.
    Keywords:  AGR2; TMED2; endoplasmic reticulum; inflammation; proteostasis
    DOI:  https://doi.org/10.15252/emmm.201810120
  2. FASEB J. 2019 May 03. fj201802626R
    Wang Q, Groenendyk J, Paskevicius T, Qin W, Kor KC, Liu Y, Hiess F, Knollmann BC, Chen SRW, Tang J, Chen XZ, Agellon LB, Michalak M.
      The endoplasmic reticulum (ER) plays a central role in cellular stress responses via mobilization of ER stress coping responses, such as the unfolded protein response (UPR). The inositol-requiring enzyme 1 IRE1a (IRE1a) is an ER stress sensor and component of the UPR. Muscle cells also have a well-developed and highly subspecialized membrane network of smooth ER called the sarcoplasmic reticulum (SR) surrounding myofibrils and specialized for Ca2+ storage, release, and uptake to control muscle excitation-contraction coupling. Here, we describe 2 distinct pools of IRE1α in cardiac and skeletal muscle cells, one localized at the perinuclear ER and the other at the junctional SR. We discovered that, at the junctional SR, calsequestrin binds to the ER luminal domain of IRE1α, inhibiting its dimerization. This novel interaction of IRE1α with calsequestrin, one of the highly abundant Ca2+ handling proteins at the junctional SR, provides new insights into the regulation of stress coping responses in muscle cells.-Wang, Q., Groenendyk, J., Paskevicius, T., Qin, W., Kor, K. C., Liu, Y., Hiess, F., Knollmann, B. C., Chen, S. R. W., Tang, J., Chen, X.-Z., Agellon, L. B., Michalak, M. Two pools of IRE1α in cardiac and skeletal muscle cells.
    Keywords:  ER stress; calcium; calsequestrin; sarcoplasmic reticulum
    DOI:  https://doi.org/10.1096/fj.201802626R
  3. JCI Insight. 2019 May 02. pii: 98101. [Epub ahead of print]4(9):
    Nakada EM, Bhakta NR, Korwin-Mihavics BR, Kumar A, Chamberlain N, Bruno SR, Chapman DG, Hoffman SM, Daphtary N, Aliyeva M, Irvin CG, Dixon AE, Woodruff PG, Amin S, Poynter ME, Desai DH, Anathy V.
      Conjugated bile acids (CBAs), such as tauroursodeoxycholic acid (TUDCA), are known to resolve the inflammatory and unfolded protein response (UPR) in inflammatory diseases, such as asthma. Whether CBAs exert their beneficial effects on allergic airway responses via 1 arm or several arms of the UPR, or alternatively through the signaling pathways for conserved bile acid receptor, remains largely unknown. We used a house dust mite-induced (HDM-induced) murine model of asthma to evaluate and compare the effects of 5 CBAs and 1 unconjugated bile acid in attenuating allergen-induced UPR and airway responses. Expression of UPR-associated transcripts was assessed in airway brushings from human patients with asthma and healthy subjects. Here we show that CBAs, such as alanyl β-muricholic acid (AβM) and TUDCA, significantly decreased inflammatory, immune, and cytokine responses; mucus metaplasia; and airway hyperresponsiveness, as compared with other CBAs in a model of allergic airway disease. CBAs predominantly bind to activating transcription factor 6α (ATF6α) compared with the other canonical transducers of the UPR, subsequently decreasing allergen-induced UPR activation and resolving allergic airway disease, without significant activation of the bile acid receptors. TUDCA and AβM also attenuated other HDM-induced ER stress markers in the lungs of allergic mice. Quantitative mRNA analysis of airway epithelial brushings from human subjects demonstrated that several ATF6α-related transcripts were significantly upregulated in patients with asthma compared with healthy subjects. Collectively, these results demonstrate that CBA-based therapy potently inhibits the allergen-induced UPR and allergic airway disease in mice via preferential binding of the canonical transducer of the UPR, ATF6α. These results potentially suggest a novel avenue to treat allergic asthma using select CBAs.
    Keywords:  Allergy; Asthma; Inflammation; Protein misfolding; Pulmonology
    DOI:  https://doi.org/10.1172/jci.insight.98101
  4. Mol Carcinog. 2019 Apr 30.
    Chalmers F, Mogre S, Son J, Blazanin N, Glick AB.
      Cancer is associated with a number of conditions such as hypoxia, nutrient deprivation, cellular redox, and pH changes that result in accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER) and trigger a stress response known as the unfolded protein response (UPR). The UPR is a conserved cellular survival mechanism mediated by the ER transmembrane proteins activating transcription factor 6, protein kinase-like endoplasmic reticulum kinase, and inositol-requiring enzyme 1α (IRE1α) that act to resolve ER stress and promote cell survival. IRE1α is a kinase/endoribonuclease (RNase) with multiple activities including unconventional splicing of the messenger RNA (mRNA) for the transcription factor X-Box Binding Protein 1 (XBP1), degradation of other mRNAs in a process called regulated IRE1α-dependent decay (RIDD) and activation of a pathway leading to c-Jun N-terminal kinase phosphorylation. Each of these outputs plays a role in the adaptive and cell death responses to ER stress. Many studies indicate an important role for XBP1 and RIDD functions in cancer and new studies suggest that these two functions of the IRE1α RNase can have opposing functions in the early and later stages of cancer pathogenesis. Finally, as more is learned about the context-dependent role of IRE1α in cancer development, specific small molecule inhibitors and activators of IRE1α could play an important role in counteracting the protective shield provided by ER stress signaling in cancer cells.
    Keywords:  X-Box Binding Protein 1; endoplasmic reticulum stress; inositol-requiring enzyme 1α; regulated IRE1α-dependent decay; unfolded protein response
    DOI:  https://doi.org/10.1002/mc.23031
  5. Biochim Biophys Acta Mol Cell Biol Lipids. 2019 Apr 24. pii: S1388-1981(19)30062-9. [Epub ahead of print]
    Fun XH, Thibault G.
      The unfolded protein response (UPR) is activated by endoplasmic reticulum (ER) stress and is designed to restore cellular homeostasis through multiple intracellular signalling pathways. In mammals, the UPR programme regulates the expression of hundreds of genes in response to signalling from ATF6, IRE1, and PERK. These three highly conserved stress sensors are activated by the accumulation of unfolded proteins within the ER. Alternatively, IRE1 and PERK sense generalised lipid bilayer stress (LBS) at the ER while ATF6 is activated by an increase of specific sphingolipids. As a result, the UPR supports cellular robustness as a broad-spectrum compensatory pathway that is achieved by deploying a tailored transcriptional programme adapted to the source of ER stress. This review summarises the current understanding of the three ER stress transducers in sensing proteotoxic stress and LBS. The plasticity of the UPR programme in the context of different sources of ER stress will also be discussed.
    Keywords:  Differential transcriptome; Endoplasmic reticulum stress; Lipid bilayer stress; Proteotoxic stress; Stress sensing mechanism; Unfolded protein response
    DOI:  https://doi.org/10.1016/j.bbalip.2019.04.009
  6. J Biol Chem. 2019 May 03. pii: jbc.RA119.008263. [Epub ahead of print]
    Pitera AP, Asuni AA, O'Connor V, Deinhardt K.
      The unfolded protein response (UPR) is commonly associated with a range of neurodegenerative diseases, and targeting UPR components has been suggested as a therapeutic strategy. The UPR surveys protein folding within the endoplasmic reticulum (ER). However, many of the misfolded proteins that accumulate in neurodegeneration are localized such that they do not directly cause ER triggers that activate this pathway. Here, using a transgenic mouse model and primary cell cultures, along with qPCR, immunoblotting and immunohistochemistry, we tested whether UPR is induced in in vivo andin vitro murine models of tauopathy that are based on expression of mutant tauP301L. We found no evidence for UPR in the rTg4510 mouse model in which mutant tau is transgenically expressed under control oftetracycline-controlled transactivator protein (tTA). This observation was supported by results from acute experiments in which neuronal cultures expressed mutant tau and accumulated misfolded cytoplasmic tau aggregates, but exhibited no UPR activation. These results suggest that the UPR is not induced as a response to tau misfolding and aggregation, despite clear evidence for progressive cellular dysfunction and degeneration. We propose that caution is needed when evaluating the implied significance of the UPR as a critical determinant across major neurodegenerative diseases.
    Keywords:  Tau protein (Tau); frontotemporal dementia; neurodegenerative disease; neuron; primary hippocampal neuron; protein misfolding; tauopathy; transgenic mice; unfolded protein response (UPR)
    DOI:  https://doi.org/10.1074/jbc.RA119.008263
  7. J Neurochem. 2019 Apr 30.
    Zhou J, Song J, Wu S.
      Endoplasmic reticulum (ER) stress has been highlighted as one of the factors involved in axon/dendrite degeneration, which is an early event in Alzheimer's (AD), Parkinson's (PD) diseases as well as in acute disorders such as ischemia and axotomy-induced retinal ganglion cell degeneration. These lines of evidence suggest critical roles of ER stress at the early stage of neurodegeneration, but the relevant mechanism is rarely exploited. In this study, we report that treatment with sublethal level of ER stressors, tunicamycin or brefeldin A, in primary rat neuronal cultures, significantly reduced dendrite arbor. Under the same treatment, either stressor reduced store-operated calcium entry (SOCE) and cytosolic calcium, [Ca 2+ ]i , which were associated with autophagic degradation of stromal interaction molecule 2 (STIM2). Knockdown of ATG7 or ATF4 completely reversed the reduction of STIM2 and significantly reversed the inhibition of SOCE under ER stress. Overexpression of STIM2 in neurons significantly prevented the ER stress-induced disruption of dendrite arbor. Altogether, our data reveal an unprecedented mechanism by which ER stress induces dendrite degeneration, that is, ER stress induces autophagic degradation of STIM2, leading to ensued SOCE inhibition and reduced [Ca 2+ ]i , resulting in trimming effect on dendrites. This article is protected by copyright. All rights reserved.
    Keywords:  Alzheimer's disease; ER stress; Parkinson's disease; autophagy; dendrites; store-operated calcium entry; stromal interaction molecule 1/2; unfolded protein response
    DOI:  https://doi.org/10.1111/jnc.14712
  8. Front Cell Dev Biol. 2019 ;7 50
    Serrano-Del Valle A, Anel A, Naval J, Marzo I.
      Over the past decades, immunotherapy has demonstrated a prominent clinical efficacy in a wide variety of human tumors. For many years, apoptosis has been considered a non-immunogenic or tolerogenic process whereas necrosis or necroptosis has long been acknowledged to play a key role in inflammation and immune-related processes. However, the new concept of "immunogenic cell death" (ICD) has challenged this traditional view and has granted apoptosis with immunogenic abilities. This paradigm shift offers clear implications in designing novel anti-cancer therapeutic approaches. To date, several screening studies have been carried out to discover bona fide ICD inducers and reveal the inherent capacity of a wide variety of drugs to induce cell death-associated exposure of danger signals and to bring about in vivo anti-cancer immune responses. Recent shreds of evidence place ER stress at the core of all the scenarios where ICD occur. Furthermore, ER stress and the unfolded protein response (UPR) have emerged as important targets in different human cancers. Notably, in multiple myeloma (MM), a lethal plasma cell disorder, the elevated production of immunoglobulins leaves these cells heavily reliant on the survival arm of the UPR. For that reason, drugs that disrupt ER homeostasis and engage ER stress-associated cell death, such as proteasome inhibitors, which are currently used for the treatment of MM, as well as novel ER stressors are intended to be promising therapeutic agents in MM. This not only holds true for their capacity to induce cell death, but also to their potential ability to activate the immunogenic arm of the ER stress response, with the ensuing exposure of danger signals. We provide here an overview of the up-to-date knowledge regarding the cell death mechanisms involved in situations of ER stress with a special focus on the connections with the drug-induced ER stress pathways that evoke ICD. We will also discuss how this could assist in optimizing and developing better immunotherapeutic approaches, especially in MM treatment.
    Keywords:  ER stress; danger-associated molecular pattern; immunogenic cell death; immunotherapy; multiple myeloma
    DOI:  https://doi.org/10.3389/fcell.2019.00050
  9. Neoplasia. 2019 Apr 24. pii: S1476-5586(18)30527-X. [Epub ahead of print]21(6): 516-532
    Yarapureddy S, Abril J, Foote J, Kumar S, Asad O, Sharath V, Faraj J, Daniel D, Dickman P, White-Collins A, Hingorani P, Sertil AR.
      Patients with metastatic or relapsed/refractory osteosarcoma (OS) have a 5-year survival rate of <30%. This has remained unchanged over several decades. One of the factors contributing to lack of improvement in survival is the development of chemoresistance. Hence, elucidating and targeting the mechanisms that promote survival against chemotherapy and lead to chemoresistance is pivotal to improving outcomes for these patients. We identified that endoplasmic reticulum (ER) stress-activated transcription factor, ATF6α, is essential for the survival of OS cells against chemotherapy induced cell death. ATF6α cleavage and activity were enhanced in OS cells compared to normal osteoblasts and knockdown of ATF6α expression enhanced sensitivity of OS cells against chemotherapy induced cell death. This was in part due to increased Bax activation. Pharmacologic inhibition or knock-down of downstream targets of ATF6α, protein disulfide isomerases (PDI) and ERO1β, a thiol oxidase that is involved in the re-oxidation of PDIs also independently induced pronounced killing of OS cells following chemotherapy. Analysis of primary tumors from OS patients reveals that patients with high levels of nuclear ATF6α: (1) also had increased expression of its downstream targets the chaperone BiP and enzyme PDI, (2) had a significant likelihood of developing metastasis at diagnosis, (3) had significantly poorer overall and progression free survival, and (4) had poorer response to chemotherapy. These findings suggest that targeting survival signaling by the ATF6α pathway in OS cells may favor eradication of refractory OS tumor cells and ATF6α could be a useful predictor for chemo-responsiveness and prognosis.
    DOI:  https://doi.org/10.1016/j.neo.2019.02.004
  10. Biochim Biophys Acta Gen Subj. 2019 Apr 24. pii: S0304-4165(19)30107-2. [Epub ahead of print]1863(7): 1210-1216
    Groenendyk J, Robinson A, Wang Q, Hu M, Tang J, Chen XZ, Mengel M, Alexander RT, Agellon LB, Michalak M.
      Chronic exposure to cyclosporine causes nephrotoxicity and organ damage. Here we show that cyclosporine nephrotoxicity in vivo is associated with the activation of the unfolded protein response (UPR) pathway to initiate tissue fibrosis. We demonstrate that cyclosporine therapy activated the IRE1α branch of the unfolded protein response (UPR) and stimulated the TGFβ1 signaling pathway in the kidneys of male mice. Co-administration of the proteostasis promoter tauroursodeoxycholic acid (TUDCA) with cyclosporine inhibited the UPR pathway in the kidneys of treated male mice as well as decreased the development of renal fibrogenesis.
    Keywords:  Cyclosporine; Fibrogenesis; Kidney disease; Proteostasis promoter; TUDCA; Unfolded protein responses
    DOI:  https://doi.org/10.1016/j.bbagen.2019.04.016
  11. Mol Cell Neurosci. 2019 Apr 24. pii: S1044-7431(19)30093-4. [Epub ahead of print]
    Gomez M, Germain D.
      The mitochondrial unfolded protein response (UPRmt) is rapidly gaining attention. While the CHOP (ATF4/5) axis of the UPRmt was the first to be described, other axes have subsequently been reported. Validation of this complex pathway in C. elegans has been extensively studied. However, validation of the UPRmt in mouse models of disease known to implicate mitochondrial reprogramming or dysfunction, such as cancer and neurodegeneration, respectively, is only beginning to emerge. This review summarizes recent findings and highlights the major role of the superoxide dismutase SOD1 in the communication between the mitochondria and the nucleus in these settings. While SOD1 has mostly been studied in the context of familial amyotrophic lateral sclerosis (fALS), recent studies suggest that SOD1 may be a potentially important mediator of the UPRmt and converge to emphasize an increasingly vital role of SOD1 as a therapeutic target in cancer.
    Keywords:  ALS; Cancer; Estrogen receptor; Mitochondria; Neurodegeneration; ROS; SIRT3; SOD1; SOD2; UPR(mt)
    DOI:  https://doi.org/10.1016/j.mcn.2019.04.003