bims-ershed 2023-06-18 papers

mBio. 2023 Jun 12. e0054023

The unfolded protein response components IRE1α and XBP1 promote human coronavirus infection.

Jessica M Oda, Andreas B den Hartigh, Shoen M Jackson, Ana R Tronco, Susan L Fink.

The cellular processes that support human coronavirus replication and contribute to the pathogenesis of severe disease remain incompletely understood. Many viruses, including coronaviruses, cause endoplasmic reticulum (ER) stress during infection. IRE1α is a component of the cellular response to ER stress that initiates non-conventional splicing of XBP1 mRNA. Spliced XBP1 encodes a transcription factor that induces the expression of ER-related targets. Activation of the IRE1α-XBP1 pathway occurs in association with risk factors for severe human coronavirus infection. In this study, we found that the human coronaviruses HCoV-OC43 (human coronavirus OC43) and SARS-CoV-2 (severe acute respiratory syndrome coronavirus-2) both robustly activate the IRE1α-XBP1 branch of the unfolded protein response in cultured cells. Using IRE1α nuclease inhibitors and genetic knockdown of IRE1α and XBP1, we found that these host factors are required for optimal replication of both viruses. Our data suggest that IRE1α supports infection downstream of initial viral attachment and entry. In addition, we found that ER stress-inducing conditions are sufficient to enhance human coronavirus replication. Furthermore, we found markedly increased XBP1 in circulation in human patients with severe coronavirus disease 2019 (COVID-19). Together, these results demonstrate the importance of IRE1α and XBP1 for human coronavirus infection.IMPORTANCEThere is a critical need to understand the cellular processes co-opted during human coronavirus replication, with an emphasis on identifying mechanisms underlying severe disease and potential therapeutic targets. Here, we demonstrate that the host proteins IRE1α and XBP1 are required for robust infection by the human coronaviruses, SARS-CoV-2 and HCoV-OC43. IRE1α and XBP1 participate in the cellular response to ER stress and are activated during conditions that predispose to severe COVID-19. We found enhanced viral replication with exogenous IRE1α activation, and evidence that this pathway is activated in humans during severe COVID-19. Together, these results demonstrate the importance of IRE1α and XBP1 for human coronavirus infection.

Keywords: ER stress; HCoV-OC43; IRE1α; SARS-CoV-2; XBP1; coronavirus; endoplasmic reticulum; unfolded protein response

DOI: https://doi.org/10.1128/mbio.00540-23

Mol Cell Biochem. 2023 Jun 13.

IRE1α: from the function to the potential therapeutic target in atherosclerosis.

Zheng-Yang Zhou, Li Wu, Yi-Fan Liu, Mu-Yao Tang, Jing-Yi Tang, Ya-Qian Deng, Lei Liu, Bin-Bin Nie, Zi-Kai Zou, Liang Huang.

Inositol requiring enzyme 1 (IRE1) is generally thought to control the most conserved pathway in the unfolded protein response (UPR). Two isoforms of IRE1, IRE1α and IRE1β, have been reported in mammals. IRE1α is a ubiquitously expressed protein whose knockout shows marked lethality. In contrast, the expression of IRE1β is exclusively restricted in the epithelial cells of the respiratory and gastrointestinal tracts, and IRE1β-knockout mice are phenotypically normal. As research continues to deepen, IRE1α was showed to be tightly linked to inflammation, lipid metabolism regulation, cell death and so on. Growing evidence also suggests an important role for IRE1α in promoting atherosclerosis (AS) progression and acute cardiovascular events through disrupting lipid metabolism balance, facilitating cells apoptosis, accelerating inflammatory responses and promoting foam cell formation. In addition, IRE1α was recognized as novel potential therapeutic target in AS prevention. This review provides some clues about the relationship between IRE1α and AS, hoping to contribute to further understanding roles of IRE1α in atherogenesis and to be helpful for the design of novel efficacious therapeutics agents targeting IRE1α-related pathways.

Keywords: Atherosclerosis; Endoplasmic reticulum stress; IRE1α; X-box binding protein 1

DOI: https://doi.org/10.1007/s11010-023-04780-6

EMBO J. 2023 Jun 12. e113908

PERK signaling promotes mitochondrial elongation by remodeling membrane phosphatidic acid.

Valerie Perea, Christian Cole, Justine Lebeau, Vivian Dolina, Kelsey R Baron, Aparajita Madhavan, Jeffery W Kelly, Danielle A Grotjahn, R Luke Wiseman.

Endoplasmic reticulum (ER) stress and mitochondrial dysfunction are linked in the onset and pathogenesis of numerous diseases. This has led to considerable interest in defining the mechanisms responsible for regulating mitochondria during ER stress. The PERK signaling arm of the unfolded protein response (UPR) has emerged as a prominent ER stress-responsive signaling pathway that regulates diverse aspects of mitochondrial biology. Here, we show that PERK activity promotes adaptive remodeling of mitochondrial membrane phosphatidic acid (PA) to induce protective mitochondrial elongation during acute ER stress. We find that PERK activity is required for ER stress-dependent increases in both cellular PA and YME1L-dependent degradation of the intramitochondrial PA transporter PRELID1. These two processes lead to the accumulation of PA on the outer mitochondrial membrane where it can induce mitochondrial elongation by inhibiting mitochondrial fission. Our results establish a new role for PERK in the adaptive remodeling of mitochondrial phospholipids and demonstrate that PERK-dependent PA regulation adapts organellar shape in response to ER stress.

Keywords: endoplasmic reticulum (ER) stress; mitochondrial morphology; phosphatidic acid; unfolded protein response (UPR)

DOI: https://doi.org/10.15252/embj.2023113908

J Neurosci Res. 2023 Jun 14.

Astrocytic deletion of protein kinase R-like ER kinase (PERK) does not affect learning and memory in aged mice but worsens outcome from experimental stroke.

Anirudhya Lahiri, James C Walton, Ning Zhang, Neil Billington, A Courtney DeVries, Gordon P Meares.

Aging is associated with cognitive decline and is the main risk factor for a myriad of conditions including neurodegeneration and stroke. Concomitant with aging is the progressive accumulation of misfolded proteins and loss of proteostasis. Accumulation of misfolded proteins in the endoplasmic reticulum (ER) leads to ER stress and activation of the unfolded protein response (UPR). The UPR is mediated, in part, by the eukaryotic initiation factor 2α (eIF2α) kinase protein kinase R-like ER kinase (PERK). Phosphorylation of eIF2α reduces protein translation as an adaptive mechanism but this also opposes synaptic plasticity. PERK, and other eIF2α kinases, have been widely studied in neurons where they modulate both cognitive function and response to injury. The impact of astrocytic PERK signaling in cognitive processes was previously unknown. To examine this, we deleted PERK from astrocytes (AstroPERKKO ) and examined the impact on cognitive functions in middle-aged and old mice of both sexes. Additionally, we tested the outcome following experimental stroke using the transient middle cerebral artery occlusion (MCAO) model. Tests of short-term and long-term learning and memory as well as of cognitive flexibility in middle-aged and old mice revealed that astrocytic PERK does not regulate these processes. Following MCAO, AstroPERKKO had increased morbidity and mortality. Collectively, our data demonstrate that astrocytic PERK has limited impact on cognitive function and has a more prominent role in the response to neural injury.

Keywords: MCAO; RRID:AB_10692650; RRID:AB_2095847; RRID:AB_2096481; RRID:AB_2107445; RRID:AB_2631098; RRID:AB_304334; RRID:Addgene_28306; RRID:IMSR_JAX:023066; RRID:IMSR_JAX:024098; RRID:SCR_002798; RRID:SCR_014210; RRID:SCR_014289; RRID:nif-0000-00280; aging; astrocytes; glia; learning and memory; protein kinase R-like ER kinase (PERK); stroke; unfolded protein response

DOI: https://doi.org/10.1002/jnr.25224

J Biol Chem. 2023 Jun 12. pii: S0021-9258(23)01943-9. [Epub ahead of print] 104915

Ubiquitin-like protein 5 is a novel player in the UPR-PERK arm and ER stress-induced cell death.

Wei Wang, Adam M Hawkridge, Yibao Ma, Bei Zhang, John B Mangrum, Zaneera H Hassan, Tianhai He, Sofiya Blat, Chunqing Guo, Huiping Zhou, Jinze Liu, Xiang-Yang Wang, Xianjun Fang.

Biological functions of the highly conserved ubiquitin-like protein 5 (UBL5) are not well understood. In C. elegans, UBL5 is induced under mitochondrial stress to mount the mitochondrial unfolded protein response (UPRmt). However, the role of UBL5 in the more prevalent endoplasmic reticulum (ER) stress-unfolded protein response (UPR) in the mammalian system is unknown. In the present work, we demonstrated that UBL5 was an ER stress-responsive protein, undergoing rapid depletion in mammalian cells and livers of mice. The ER stress-induced UBL5 depletion was mediated by proteasome-dependent yet ubiquitin-independent proteolysis. Activation of the protein kinase R-like endoplasmic reticulum kinase (PERK) arm of the UPR was essential and sufficient for inducing UBL5 degradation. RNA-Seq analysis of UBL5-regulated transcriptome revealed that multiple death pathways were activated in UBL5-silenced cells. In agreement with this, UBL5 knockdown induced severe apoptosis in culture and suppressed tumorigenicity of cancer cells in vivo. Furthermore, overexpression of UBL5 protected specifically against ER stress-induced apoptosis. These results identify UBL5 as a physiologically relevant survival regulator that is proteolytically depleted by the UPR-PERK pathway, linking ER stress to cell death.

Keywords: ER stress; PERK; UBL5; UPR; apoptosis; cell survival; proteasome degradation; ubiquitin-independent proteasome system

DOI: https://doi.org/10.1016/j.jbc.2023.104915

Cell Rep. 2023 Jun 13. pii: S2211-1247(23)00643-5. [Epub ahead of print]42(6): 112632

Nuclear translocation of an aminoacyl-tRNA synthetase may mediate a chronic "integrated stress response".

Julia A Jones, Na Wei, Haissi Cui, Yi Shi, Guangsen Fu, Navin Rauniyar, Ryan Shapiro, Yosuke Morodomi, Nadine Berenst, Calin Dan Dumitru, Sachiko Kanaji, John R Yates, Taisuke Kanaji, Xiang-Lei Yang.

Various stress conditions are signaled through phosphorylation of translation initiation factor eukaryotic initiation factor 2α (eIF2α) to inhibit global translation while selectively activating transcription factor ATF4 to aid cell survival and recovery. However, this integrated stress response is acute and cannot resolve lasting stress. Here, we report that tyrosyl-tRNA synthetase (TyrRS), a member of the aminoacyl-tRNA synthetase family that responds to diverse stress conditions through cytosol-nucleus translocation to activate stress-response genes, also inhibits global translation. However, it occurs at a later stage than eIF2α/ATF4 and mammalian target of rapamycin (mTOR) responses. Excluding TyrRS from the nucleus over-activates translation and increases apoptosis in cells under prolonged oxidative stress. Nuclear TyrRS transcriptionally represses translation genes by recruiting TRIM28 and/or NuRD complex. We propose that TyrRS, possibly along with other family members, can sense a variety of stress signals through intrinsic properties of this enzyme and strategically located nuclear localization signal and integrate them by nucleus translocation to effect protective responses against chronic stress.

Keywords: CP: Cell biology; CP: Molecular biology; aminoacyl-tRNA synthetase; cell survival; oxidative stress; stress response; transcriptional regulation; translation inhibition

DOI: https://doi.org/10.1016/j.celrep.2023.112632