bims-unfpre 2022-04-17 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2022‒04‒17
eight papers selected by
Susan Logue
University of Manitoba

Human cDC1 display constitutive activation of the UPR Sensor IRE1.
Loss of Function of WFS1 Causes ER Stress-Mediated Inflammation in Pancreatic Beta-Cells.
Suppression of RNF213, a susceptibility gene for moyamoya disease, inhibits endoplasmic reticulum stress through SEL1L upregulation.
Abietic acid alleviates endoplasmic reticulum stress and lipid accumulation in human primary hepatocytes through the AMPK/ORP150 signaling.
The Role of Endoplasmic Reticulum Stress and NLRP3 Inflammasome in Liver Disorders.
Preventing unfolded protein response-induced ion channel dysregulation to treat arrhythmias.
Mitochondrial calpain-5 truncates caspase-4 during endoplasmic reticulum stress.
Calcineurin/NFATc2 and PI3K/AKT signaling maintains β-cell identity and function during metabolic and inflammatory stress.

Eur J Immunol. 2022 Apr 13.

Human cDC1 display constitutive activation of the UPR Sensor IRE1.

Paulina García-González, Dominique Fernández, Diane Gutiérrez, Mauro Parra-Cordero, Fabiola Osorio.

  The intracellular mechanisms safeguarding dendritic cell (DC) function are of biomedical interest in several immune-related diseases. Type 1 conventional DCs (cDC1s) are prominent targets of immunotherapy typified by constitutive activation of the unfolded protein response (UPR) sensor IRE1. Through its RNase domain, IRE1 regulates key processes in cDC1s including survival, endoplasmic reticulum architecture and function. However, most evidence linking IRE1 RNase with cDC1 biology emerges from mouse studies and it is currently unknown whether human cDC1s also activate the enzyme to preserve cellular homeostasis. In this work, we report that human cDC1s constitutively activate IRE1 RNase in steady-state, which is evidenced by marked expression of IRE1, XBP1s and target genes, and low levels of mRNA substrates of the IRE1 RNase domain. On a functional level, pharmacological inhibition of the IRE1 RNase domain curtailed IL-12 and TNF production by cDC1s upon stimulation with toll-like receptor agonists. Altogether, this work demonstrates that activation of the IRE1/XBP1s axis is a conserved feature of cDC1s across species and suggests that the UPR sensor may also play a relevant role in the biology of the human lineage. This article is protected by copyright. All rights reserved.

Keywords:  DC activation; IRE1; UPR; XBP1s; cDC1s

DOI:  https://doi.org/10.1002/eji.202149774
Front Endocrinol (Lausanne). 2022 ;13 849204

Loss of Function of WFS1 Causes ER Stress-Mediated Inflammation in Pancreatic Beta-Cells.

Shuntaro Morikawa, Lindsey Blacher, Chinyere Onwumere, Fumihiko Urano.

  Wolfram syndrome is a rare genetic disorder characterized by juvenile-onset diabetes mellitus, optic nerve atrophy, hearing loss, diabetes insipidus, and progressive neurodegeneration. Pathogenic variants in the WFS1 gene are the main causes of Wolfram syndrome. WFS1 encodes a transmembrane protein localized to the endoplasmic reticulum (ER) and regulates the unfolded protein response (UPR). Loss of function of WFS1 leads to dysregulation of insulin production and secretion, ER calcium depletion, and cytosolic calpains activation, resulting in activation of apoptotic cascades. Although the terminal UPR has been shown to induce inflammation that accelerates pancreatic β-cell dysfunction and death in diabetes, the contribution of pancreatic β-cell inflammation to the development of diabetes in Wolfram syndrome has not been fully understood. Here we show that WFS1-deficiency enhances the gene expression of pro-inflammatory cytokines and chemokines, leading to cytokine-induced ER-stress and cell death in pancreatic β-cells. PERK and IRE1α pathways mediate high glucose-induced inflammation in a β-cell model of Wolfram syndrome. M1-macrophage infiltration and hypervascularization are seen in the pancreatic islets of Wfs1 whole-body knockout mice, demonstrating that WFS1 regulates anti-inflammatory responses in pancreatic β-cells. Our results indicate that inflammation plays an essential role in the progression of β-cell death and diabetes in Wolfram syndrome. The pathways involved in ER stress-mediated inflammation provide potential therapeutic targets for the treatment of Wolfram syndrome.

Keywords:  Wolfram syndrome; diabetes; endoplasmic reticulum stress; inflammation; macrophage; unfolded protein response

DOI:  https://doi.org/10.3389/fendo.2022.849204
Biochem Biophys Res Commun. 2022 Apr 06. pii: S0006-291X(22)00522-8. [Epub ahead of print]609 62-68

Suppression of RNF213, a susceptibility gene for moyamoya disease, inhibits endoplasmic reticulum stress through SEL1L upregulation.

Sharif Ahmed, Toshiyuki Habu, Jiyeong Kim, Hiroko Okuda, Shinji Oikawa, Mariko Murata, Akio Koizumi, Hatasu Kobayashi.

  RNF213, a susceptibility gene for moyamoya disease, is associated with stress responses to various stressors. We previously reported that Rnf213 knockout (KO) mitigated endoplasmic reticulum (ER) stress-induced diabetes in the Akita mouse model of diabetes. However, the role of RNF213 in ER stress regulation remains unknown. In the present study, RNF213 knockdown significantly inhibited the upregulation of ER stress markers (CHOP and spliced XBP1) by chemical ER stress-inducers in HeLa cells. Levels of SEL1L, a critical molecule in ER-associated degradation (ERAD), were increased by RNF213 knockdown, and SEL1L knockdown prevented the inhibitory effect of RNF213 suppression on ER stress in HeLa cells, indicating SEL1L involvement in this inhibition of ER stress. SEL1L upregulation was also confirmed in pancreatic islets of Rnf213 KO/Akita mice and in Rnf213 KO mouse embryonic fibroblasts. Additionally, RNF213 suppression increased levels of HRD1, which forms a complex with SEL1L to degrade misfolded protein in cells under ER stress. In conclusion, we demonstrate that RNF213 depletion inhibits ER stress possibly through elevation of the SEL1L-HRD1 complex, thereby promoting ERAD in vitro and in vivo.

Keywords:  Endoplasmic reticulum stress; HRD1; Moyamoya disease; RNF213; SEL1L

DOI:  https://doi.org/10.1016/j.bbrc.2022.04.007
Biochem Biophys Res Commun. 2022 Apr 04. pii: S0006-291X(22)00525-3. [Epub ahead of print]608 142-148

Abietic acid alleviates endoplasmic reticulum stress and lipid accumulation in human primary hepatocytes through the AMPK/ORP150 signaling.

Tae Woo Jung, Ju-Cheol Jeong, Seung Yeon Park, Wonjun Cho, Heeseung Oh, Hyun Jung Lee, Ahmet Hacimuftuoglu, A M Abd El-Aty, Joon Seok Bang, Ji Hoon Jeong.

  Abietic acid (AA), the main component of pine resin that has been traditionally used as Asian medicine, has been reported to demonstrate anti-inflammatory activities. Despite this, little is known about the effects of AA on hepatic endoplasmic reticulum (ER) stress and lipid metabolism. This study investigated the impacts of AA on ER stress and steatosis in in vitro obesity models. We found that Treatment with AA reduced lipid deposition and lipogenesis-related proteins expression in human primary hepatocytes. Augmented expression of ER stress markers (phospho-eukaryotic initiation factor-2α (eIF2α) and C/EBP homologous protein (CHOP)) in palmitate-treated hepatocytes were reversed by AA treatment. Further, AA treatment increased the expression of phospho-AMPK and oxygen-regulated protein 150 (ORP150) in hepatocytes. siRNA-associated knockdown of AMPK or ORP150 expression reduced the effects of AA on not only hepatic ER stress but also lipogenesis and apoptosis. These results denote that AA attenuates lipid accumulation in hepatocytes in the presence of palmitate through the suppression of ER stress by AMPK/ORP150 signaling. AA could be a potential candidate for treating non-alcoholic fatty liver disease.

Keywords:  AMPK; Abietic acid; ER stress; NAFLD; ORP150

DOI:  https://doi.org/10.1016/j.bbrc.2022.04.010
Int J Mol Sci. 2022 Mar 24. pii: 3528. [Epub ahead of print]23(7):

The Role of Endoplasmic Reticulum Stress and NLRP3 Inflammasome in Liver Disorders.

Xueqin Lu, Haitao Huang, Xiaodi Fu, Chaoran Chen, Huiyang Liu, Honggang Wang, Dongdong Wu.

  The endoplasmic reticulum (ER) is a key organelle responsible for the synthesis, modification, folding and assembly of proteins; calcium storage; and lipid synthesis. When ER homeostatic balance is disrupted by a variety of physiological and pathological factors-such as glucose deficiency, environmental toxins, Ca2+ level changes, etc.-ER stress can be induced. Abnormal ER stress can be involved in many diseases. NOD-like receptor family pyrin domain-containing 3 (NLRP3), an intracellular receptor, can perceive internal and external stimuli. It binds to apoptosis-associated speck-like protein containing a CARD (ASC) and caspase-1 to assemble into a protein complex called the NLRP3 inflammasome. Evidence indicates that ER stress and the NLRP3 inflammasome participate in many pathological processes; however, the exact mechanism remains to be understood. In this review, we summarized the role of ER stress and the NLRP3 inflammasome in liver disorders and analyzed the mechanisms, to provide references for future related research.

Keywords:  NLRP3 inflammasome; endoplasmic reticulum stress; hepatic ischemia–reperfusion; hepatotoxicity; liver injury; nonalcoholic fatty liver disease

DOI:  https://doi.org/10.3390/ijms23073528
Trends Mol Med. 2022 Apr 10. pii: S1471-4914(22)00074-0. [Epub ahead of print]

Preventing unfolded protein response-induced ion channel dysregulation to treat arrhythmias.

Man Liu, Gyeoung-Jin Kang, Samuel C Dudley.

  Cardiomyopathies are associated with arrhythmias and cardiac ion channel downregulation. This downregulation is arrhythmogenic. Paradoxically, antiarrhythmic therapies are based on ion channel-blocking drugs that further downregulate these channels and exhibit proarrhythmic risk. Recent studies have shown that inhibition of the protein kinase RNA-like ER kinase (PERK) arm of the unfolded protein response (UPR) prevents select cardiac ion channel downregulation and plays a protective role against arrhythmias. Prevention of ion channel downregulation represents as a novel therapeutic strategy to treat arrhythmias in myocardial infarction and heart failure.

Keywords:  cardiac ion channel; heart failure; mRNA degradation; myocardial infarction; therapy

DOI:  https://doi.org/10.1016/j.molmed.2022.03.006
Biochem Biophys Res Commun. 2022 Mar 31. pii: S0006-291X(22)00499-5. [Epub ahead of print]608 156-162

Mitochondrial calpain-5 truncates caspase-4 during endoplasmic reticulum stress.

Yusaku Chukai, Ginga Ito, Masahide Konno, Yuri Sakata, Taku Ozaki.

  Calpains are cysteine proteases activated in response to intracellular calcium signaling. Activated calpains regulate various cellular functions by degrading substrate molecules in a site-specific manner. Although most calpains are localized in the cytosol, we previously reported that calpain-5 exists in the mitochondria. The mitochondrial calpain-5 is activated during endoplasmic reticulum (ER) stress. However, the substrate of calpain-5, as well as the physiological significance of calpain-5 activation, has not yet been elucidated. In the present study, we treated HeLa cells with A23187, tunicamycin, or hydrogen peroxide to induce intracellular calcium increase, resulting in cell death. The cells treated with A23187 or tunicamycin exhibited the activation of calpain-5 and truncation of caspase-4. The truncation of caspase-4 was inhibited by the repression of calpain-5 expression with the appropriate siRNA. Additionally, both calpain-5 and caspase-4 were observed in the mitochondria. Our study is the first to demonstrate that the activation of mitochondrial calpain-5 triggers the truncation of caspase-4, suggesting that mitochondrial calpain-5 regulates the downstream pathway of caspase-4, including cell death and the inflammatory cascade. The results of the present study provide new insights into ER-stress-related diseases such as Alzheimer's disease and cancer. These perspectives allow us to propose new therapeutic strategies such as the development of inhibitors or activators of calpain-5, which may be useful in the development of treatment for ER-stress-related diseases.

Keywords:  Calcium; Calpain; Caspase; Endoplasmic reticulum stress; HeLa cell; Mitochondria

DOI:  https://doi.org/10.1016/j.bbrc.2022.03.156
iScience. 2022 Apr 15. 25(4): 104125

Calcineurin/NFATc2 and PI3K/AKT signaling maintains β-cell identity and function during metabolic and inflammatory stress.

Carly M Darden, Srividya Vasu, Jordan Mattke, Yang Liu, Christopher J Rhodes, Bashoo Naziruddin, Michael C Lawrence.

  Pancreatic islets respond to metabolic and inflammatory stress by producing hormones and other factors that induce adaptive cellular and systemic responses. Here we show that intracellular Ca2+ ([Ca2+]i) and ROS signals generated by high glucose and cytokine-induced ER stress activate calcineurin (CN)/NFATc2 and PI3K/AKT to maintain β-cell identity and function. This was attributed in part by direct induction of the endocrine differentiation gene RFX6 and suppression of several β-cell "disallowed" genes, including MCT1. CN/NFATc2 targeted p300 and HDAC1 to RFX6 and MCT1 promoters to induce and suppress gene transcription, respectively. In contrast, prolonged exposure to stress, hyperstimulated [Ca2+]i, or perturbation of CN/NFATc2 resulted in downregulation of RFX6 and induction of MCT1. These findings reveal that CN/NFATc2 and PI3K/AKT maintain β-cell function during acute stress, but β-cells dedifferentiate to a dysfunctional state upon loss or exhaustion of Ca2+/CN/NFATc2 signaling. They further demonstrate the utility of targeting CN/NFATc2 to restore β-cell function.

Keywords:  Cell biology; Diabetology; Endocrinology; Molecular biology; Molecular interaction

DOI:  https://doi.org/10.1016/j.isci.2022.104125