bims-ershed 2023-03-05 papers

bims-ershed

Biomed News

on ER Stress in Health and Diseases

Issue of 2023–03–05
five papers selected by
Matías Eduardo González Quiroz, Worker’s Hospital

VMP1 affects endoplasmic reticulum stress sensitivity via differential modulation of the three unfolded protein response arms.
GLI1, a novel target of the ER stress regulator p97/VCP, promotes ATF6f-mediated activation of XBP1.
IRE1α arm of unfolded protein response in muscle-specific TGF-β signaling-mediated regulation of muscle cell immunological properties.
ATF6β Deficiency Elicits Anxiety-like Behavior and Hyperactivity Under Stress Conditions.
PERK inhibitor, GSK2606414, ameliorates neuropathological damage, memory and motor functional impairments in cerebral ischemia via PERK/p-eIF2ɑ/ATF4/CHOP signaling.

Cell Rep. 2023 Mar 03. pii: S2211-1247(23)00220-6. [Epub ahead of print]42(3): 112209

VMP1 affects endoplasmic reticulum stress sensitivity via differential modulation of the three unfolded protein response arms.

Tao Li, Hongyu Zhao, Gaofeng Guo, Shuwei Xia, Likun Wang.

  Consisting of three signaling pathways, the unfolded protein response (UPR) can be either protective or detrimental to cells that undergo ER stress. Elaborate regulation of the UPR is key to the cell-fate decision, but how it is achieved remains vague. Here, by studying cells deficient in vacuole membrane protein 1 (VMP1), a UPR regulator, we report a model of UPR regulation in which the three pathways are divergently controlled. Under basal conditions, calcium binding specifically activates PERK. Under ER stress, ER-mitochondria interaction-induced mitochondrial stress cooperates with PERK to suppress IRE1α and ATF6 by decelerating global protein synthesis. Such sophisticated regulation commits limited activation of the UPR yet refrains from UPR hyperactivation, protecting cells from chronic ER stress despite decreasing cell proliferation. Therefore, our study reveals interorganelle-interaction-dependent and calcium-dependent regulation of the UPR that dictates cell fate.

Keywords:  CP: Cell biology; ER stress; ER stress resistance; ER-mitochondria contact; VMP1; calcium; integrated stress response; mitochondrial stress; unfolded protein response

DOI:  https://doi.org/10.1016/j.celrep.2023.112209
Biochim Biophys Acta Gene Regul Mech. 2023 Feb 24. pii: S1874-9399(23)00019-6. [Epub ahead of print] 194924

GLI1, a novel target of the ER stress regulator p97/VCP, promotes ATF6f-mediated activation of XBP1.

Luciana L Almada, Kim Barroso, Sandhya Sen, Murat Toruner, Ashley N Sigafoos, Glancis L Raja Arul, David R Pease, Renzo E Vera, Rachel L O Olson, Holger W Auner, Rémy Pedeux, Juan L Iovanna, Eric Chevet, Martin E Fernandez-Zapico.

  Upon accumulation of improperly folded proteins in the Endoplasmic Reticulum (ER), the Unfolded Protein Response (UPR) is triggered to restore ER homeostasis. The induction of stress genes is a sine qua non condition for effective adaptive UPR. Although this requirement has been extensively described, the mechanisms underlying this process remain in part uncharacterized. Here, we show that p97/VCP, an AAA+ ATPase known to contribute to ER stress-induced gene expression, regulates the transcription factor GLI1, a primary effector of Hedgehog (Hh) signaling. Under basal (non-ER stress) conditions, GLI1 is repressed by a p97/VCP-HDAC1 complex while upon ER stress GLI1 is induced through a mechanism requiring both USF2 binding and increase histone acetylation at its promoter. Interestingly, the induction of GLI1 was independent of ligand-regulated Hh signaling. Further analysis showed that GLI1 cooperates with ATF6f to induce promoter activity and expression of XBP1, a key transcription factor driving UPR. Overall, our work demonstrates a novel role for GLI1 in the regulation of ER stress gene expression and defines the interplay between p97/VCP, HDAC1 and USF2 as essential players in this process.

Keywords:  ER stress; GLI1; HDAC1; Hedgehog; UPR; USF2; p97/VCP

DOI:  https://doi.org/10.1016/j.bbagrm.2023.194924
Cell Mol Biol Lett. 2023 Feb 27. 28(1): 15

IRE1α arm of unfolded protein response in muscle-specific TGF-β signaling-mediated regulation of muscle cell immunological properties.

Jiangwei Xiao, Jingwen Huang, Xiaoting Jian, Han Wang, Haiqiang Lan, Zhaohong Liao, Ruicai Gu, Jijie Hu, Hua Liao.

  Endoplasmic reticulum stress (ERS) and the unfolded protein response (UPR) are involved in various muscle pathological states. The IRE1α arm of UPR can affect immunological properties of myofiber through restraining p38 mitogen-activated protein kinases (MAPK) activation under inflammatory milieu. However, the relevant pathway molecules regulating the initiation of the IRE1α arm in myofiber remain unclear. In this work, expression of transforming growth factor-beta (TGF-β) and TGF-β receptor II (TGF-βr2), and UPR pathway activation were examined in cardiotoxin (CTX)-damaged mouse muscle, which revealed the activation of TGF-β signaling and UPR in CTX-damaged muscle and in regenerating myofibers. Using control or transgenic mice with TGF-βr2 deleted in skeletal muscle (SM TGF-βr2-/-) and the derived primary differentiating myogenic precursor cells (MPCs) treated with/without ERS activator or inhibitor, IRE1α pathway inhibitor, or TGF-β signaling activator, this study further revealed an essential role of intrinsic TGF-β signaling in regulating muscle cell to express inflammation-related molecules including H-2Kb, H2-Eα, TLR3, and special myokines. TGF-β signaling prompted UPR IRE1α arm and restrained p38 MAPK activation in myofiber under inflammatory milieu. This study uncovers a previously unrecognized function of TGF-β signaling acting as an upstream factor controlling myofiber immune capacities in the inflamed state through the UPR-IRE1α-p38 MAPK pathway.

Keywords:  IRE1α; Inflammation; Myofiber; TGF-β; UPR; p38 MAPK

DOI:  https://doi.org/10.1186/s11658-023-00429-w
Neurochem Res. 2023 Feb 28.

ATF6β Deficiency Elicits Anxiety-like Behavior and Hyperactivity Under Stress Conditions.

Takashi Tanaka, Dinh Thi Nguyen, Nichakarn Kwankaew, Megumi Sumizono, Reika Shinoda, Hiroshi Ishii, Mika Takarada-Iemata, Tsuyoshi Hattori, Seiichi Oyadomari, Nobuo Kato, Kazutoshi Mori, Osamu Hori.

  Activating transcription factor 6 (ATF6) is an endoplasmic reticulum (ER) stress-regulated transcription factor that induces expression of major molecular chaperones in the ER. We recently reported that ATF6β, a subtype of ATF6, promoted survival of hippocampal neurons exposed to ER stress and excitotoxicity, at least in part by inducing expression of calreticulin, an ER molecular chaperone with high Ca2+-binding capacity. In the present study, we demonstrate that ATF6β deficiency in mice also decreases calreticulin expression and increases expression of glucose-regulated protein 78, another ER molecular chaperone, in emotional brain regions such as the prefrontal cortex (PFC), hypothalamus, hippocampus, and amygdala. Comprehensive behavioral analyses revealed that Atf6b-/- mice exhibit anxiety-like behavior in the light/dark transition test and hyperactivity in the forced swim test. Consistent with these results, PFC and hypothalamic corticotropin-releasing hormone (CRH) expression was increased in Atf6b-/- mice, as was circulating corticosterone. Moreover, CRH receptor 1 antagonism alleviated anxiety-like behavior in Atf6b-/- mice. These findings suggest that ATF6β deficiency produces anxiety-like behavior and hyperactivity via a CRH receptor 1-dependent mechanism. ATF6β could play a role in psychiatric conditions in the emotional centers of the brain.

Keywords:  Activating transcription factor 6β; Anxiety-like behavior; Endoplasmic reticulum stress; Hyperactivity; Hypothalamic-pituitary-adrenal axis

DOI:  https://doi.org/10.1007/s11064-023-03900-4
Metab Brain Dis. 2023 Feb 27.

PERK inhibitor, GSK2606414, ameliorates neuropathological damage, memory and motor functional impairments in cerebral ischemia via PERK/p-eIF2ɑ/ATF4/CHOP signaling.

Neha Dhir, Ashish Jain, Amit Raj Sharma, Ajay Prakash, Bishan Das Radotra, Bikash Medhi.

  The protein kinase R-like endoplasmic reticulum kinase/eukaryotic initiation factor 2ɑ (PERK/eIF2α), the branch of unfolded protein response (UPR), is responsible for transient arrest in translation to counter the enhanced levels of misfolded or unfolded proteins in the endoplasmic reticulum (ER) following any acute condition. In neurological disorders, overactivation of PERK-P/eIF2-P signaling, leads to a prolonged decline in global protein synthesis resulting in synaptic failure and neuronal death. Our study has shown, PERK/ATF4/CHOP pathway gets activated following cerebral ischemia in rats. We have further demonstrated, PERK inhibitor, GSK2606414 ameliorates ischemia induced neuronal damage by preventing additional neuronal loss, minimizing brain infarct, reducing brain edema, and preventing neurological symptoms from appearing. GSK2606414 was found to improve the neurobehavioral deficits and reduce the pyknotic neurons in ischemic rats. Also, it decreased glial activation and apoptotic protein mRNA expression while enhanced the synaptic protein mRNA expression in rat brain following cerebral ischemia. In conclusion, our findings suggest that PERK/ATF4/CHOP activation play a vital role in cerebral ischemia. Thus, PERK inhibitor, GSK2606414 might be a potential neuroprotective agent in cerebral ischemia.

Keywords:  Cerebral ischemia; GSK2606414; Middle cerebral artery occlusion; PERK inhibitor; Unfolded protein response

DOI:  https://doi.org/10.1007/s11011-023-01183-w