bims-unfpre 2020-03-08 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2020–03–08
eight papers selected by
Susan Logue, University of Manitoba

IRE1α Promotes Zika Virus Infection via XBP1.
Endoplasmic Reticulum Stress Signaling in Cancer Cells.
Designing Novel Therapies to Mend Broken Hearts: ATF6 and Cardiac Proteostasis.
The Emerging Roles of Endoplasmic Reticulum Stress in Balancing Immunity and Tolerance in Health and Diseases: Mechanisms and Opportunities.
ATF4-Dependent NRF2 Transcriptional Regulation Promotes Antioxidant Protection during Endoplasmic Reticulum Stress.
Mitochondrial stress is relayed to the cytosol by an OMA1-DELE1-HRI pathway.
Emerging roles of the unfolded protein response (UPR) in the nervous system: A link with adaptive behavior to environmental stress?
Delivery of phosphatidylethanolamine blunts stress in hepatoma cells exposed to elevated palmitate by targeting the endoplasmic reticulum.

Viruses. 2020 Mar 03. pii: E278. [Epub ahead of print]12(3):

IRE1α Promotes Zika Virus Infection via XBP1.

Elena P Kolpikova, Ana R Tronco, Andreas B den Hartigh, Konner J Jackson, Takao Iwawaki, Susan L Fink.

  Zika virus (ZIKV) is an emergent member of the Flaviviridae family which causes severe congenital defects and other major sequelae, but the cellular processes that support ZIKV replication are incompletely understood. Related flaviviruses use the endoplasmic reticulum (ER) as a membranous platform for viral replication and induce ER stress during infection. Our data suggest that ZIKV activates IRE1α, a component of the cellular response to ER stress. IRE1α is an ER-resident transmembrane protein that possesses a cytosolic RNase domain. Upon activation, IRE1α initiates nonconventional cytoplasmic splicing of XBP1 mRNA. Spliced XBP1 encodes a transcription factor, which upregulates ER-related targets. We find that ZIKV infection induces XBP1 mRNA splicing and induction of XBP1 target genes. Small molecule inhibitors of IRE1α, including those specific for the nuclease function, prevent ZIKV-induced cytotoxicity, as does genetic disruption of IRE1α. Optimal ZIKV RNA replication requires both IRE1α and XBP1. Spliced XBP1 has been described to cause ER expansion and remodeling and we find that ER redistribution during ZIKV infection requires IRE1α nuclease activity. Finally, we demonstrate that inducible genetic disruption of IRE1α and XBP1 impairs ZIKV replication in a mouse model of infection. Together, our data indicate that the ER stress response component IRE1α promotes ZIKV infection via XBP1 and may represent a potential therapeutic target.

Keywords:  ER stress; IRE1α; XBP1; Zika virus; endoplasmic reticulum; flavivirus; unfolded protein response

DOI:  https://doi.org/10.3390/v12030278
Am J Pathol. 2020 Feb 26. pii: S0002-9440(20)30088-2. [Epub ahead of print]

Endoplasmic Reticulum Stress Signaling in Cancer Cells.

Scott A Oakes.

To survive, cancers cells must resist numerous internal and environmental insults associated with neoplasia that jeopardize proteostasis within the endoplasmic reticulum (ER). Solid and hematopoietic tumors often experience genomic instability, oncogene activation, increased protein secretion demands, and somatic mutations in proteins handled by the secretory pathway that impede their folding. Invasion or metastasis into foreign environments can expose tumor cells to hypoxia, oxidative stress, lack of growth signals, inadequate amino acid supplies, glucose deprivation, and lactic acidosis, all of which pose challenges for protein processing in the ER. Together, these conditions can promote the buildup of misfolded proteins in the ER to cause "ER stress," which then activates the unfolded protein response (UPR). An intracellular signaling network largely initiated by three ER transmembrane proteins, the UPR constantly surveils protein folding conditions within the ER lumen and when necessary initiates counteractive measures to maintain ER homeostasis. Under mild or moderate levels of ER stress, the homeostatic UPR (hUPR) sets in motion transcriptional and translational changes that promote cell adaption and survival. However, if these processes are unsuccessful at resolving ER stress, a terminal UPR (tUPR) program dominates and actively signals cell suicide. This article summarizes the mounting evidence that cancer cells are predisposed to ER stress and vulnerable to targeted interventions against ongoing UPR signaling.

DOI: https://doi.org/10.1016/j.ajpath.2020.01.010
Cells. 2020 Mar 03. pii: E602. [Epub ahead of print]9(3):

Designing Novel Therapies to Mend Broken Hearts: ATF6 and Cardiac Proteostasis.

Erik A Blackwood, Alina S Bilal, Winston T Stauffer, Adrian Arrieta, Christopher C Glembotski.

  The heart exhibits incredible plasticity in response to both environmental and genetic alterations that affect workload. Over the course of development, or in response to physiological or pathological stimuli, the heart responds to fluctuations in workload by hypertrophic growth primarily by individual cardiac myocytes growing in size. Cardiac hypertrophy is associated with an increase in protein synthesis, which must coordinate with protein folding and degradation to allow for homeostatic growth without affecting the functional integrity of cardiac myocytes (i.e., proteostasis). This increase in the protein folding demand in the growing cardiac myocyte activates the transcription factor, ATF6 (activating transcription factor 6α, an inducer of genes that restore proteostasis. Previously, ATF6 has been shown to induce ER-targeted proteins functioning primarily to enhance ER protein folding and degradation. More recent studies, however, have illuminated adaptive roles for ATF6 functioning outside of the ER by inducing non-canonical targets in a stimulus-specific manner. This unique ability of ATF6 to act as an initial adaptive responder has bolstered an enthusiasm for identifying small molecule activators of ATF6 and similar proteostasis-based therapeutics.

Keywords:  ATF6; cardiac myocyte; cardiomyopathy; hypertrophy; proteostasis; small molecule; therapy; transcriptional regulation; unfolded protein response (UPR)

DOI:  https://doi.org/10.3390/cells9030602
Front Immunol. 2019 ;10 3154

The Emerging Roles of Endoplasmic Reticulum Stress in Balancing Immunity and Tolerance in Health and Diseases: Mechanisms and Opportunities.

Anqi Li, No-Joon Song, Brian P Riesenberg, Zihai Li.

  The endoplasmic reticulum (ER) is an organelle equipped with mechanisms for proper protein folding, trafficking, and degradation to maintain protein homeostasis in the secretory pathway. As a defense mechanism, perturbation of ER proteostasis by ER stress agents activates a cascade of signaling pathways from the ER to the nucleus known as unfolded protein response (UPR). The primary goal of UPR is to induce transcriptional and translational programs to restore ER homeostasis for cell survival. As such, defects in UPR signaling have been implicated as a key contributor to multiple diseases including metabolic diseases, degenerative diseases, inflammatory disorders, and cancer. Growing evidence support the critical role of ER stress in regulating the fate as well as the magnitude of the immune response. Moreover, the availability of multiple UPR pharmacological inhibitors raises the hope that targeting UPR can be a new strategy for immune modulation and immunotherapy of diseases. This paper reviews the principal mechanisms by which ER stress affects immune cell biology and function, with a focus of discussion on UPR-associated immunopathology and the development of potential ER stress-targeted therapeutics.

Keywords:  diseases; endoplasmic reticulum stress; immunity; inhibitors; therapeutics

DOI:  https://doi.org/10.3389/fimmu.2019.03154
Cancers (Basel). 2020 Mar 01. pii: E569. [Epub ahead of print]12(3):

ATF4-Dependent NRF2 Transcriptional Regulation Promotes Antioxidant Protection during Endoplasmic Reticulum Stress.

Carmen Sarcinelli, Helena Dragic, Marie Piecyk, Virginie Barbet, Cédric Duret, Audrey Barthelaix, Carole Ferraro-Peyret, Joelle Fauvre, Toufic Renno, Cédric Chaveroux, Serge N Manié.

  Endoplasmic reticulum (ER) stress generates reactive oxygen species (ROS) that induce apoptosis if left unabated. To limit oxidative insults, the ER stress PKR-like endoplasmic reticulum Kinase (PERK) has been reported to phosphorylate and activate nuclear factor erythroid 2-related factor 2 (NRF2). Here, we uncover an alternative mechanism for PERK-mediated NRF2 regulation in human cells that does not require direct phosphorylation. We show that the activation of the PERK pathway rapidly stimulates the expression of NRF2 through activating transcription factor 4 (ATF4). In addition, NRF2 activation is late and largely driven by reactive oxygen species (ROS) generated during late protein synthesis recovery, contributing to protecting against cell death. Thus, PERK-mediated NRF2 activation encompasses a PERK-ATF4-dependent control of NRF2 expression that contributes to the NRF2 protective response engaged during ER stress-induced ROS production.

Keywords:  ATF4; ER stress; NRF2; PERK; ROS

DOI:  https://doi.org/10.3390/cancers12030569
Nature. 2020 Mar 04.

Mitochondrial stress is relayed to the cytosol by an OMA1-DELE1-HRI pathway.

Xiaoyan Guo, Giovanni Aviles, Yi Liu, Ruilin Tian, Bret A Unger, Yu-Hsiu T Lin, Arun P Wiita, Ke Xu, M Almira Correia, Martin Kampmann.

In mammalian cells, mitochondrial dysfunction triggers the integrated stress response, in which the phosphorylation of eukaryotic translation initiation factor 2α (eIF2α) results in the induction of the transcription factor ATF41-3. However, how mitochondrial stress is relayed to ATF4 is unknown. Here we show that HRI is the eIF2α kinase that is necessary and sufficient for this relay. In a genome-wide CRISPR interference screen, we identified factors upstream of HRI: OMA1, a mitochondrial stress-activated protease; and DELE1, a little-characterized protein that we found was associated with the inner mitochondrial membrane. Mitochondrial stress stimulates OMA1-dependent cleavage of DELE1 and leads to the accumulation of DELE1 in the cytosol, where it interacts with HRI and activates the eIF2α kinase activity of HRI. In addition, DELE1 is required for ATF4 translation downstream of eIF2α phosphorylation. Blockade of the OMA1-DELE1-HRI pathway triggers an alternative response in which specific molecular chaperones are induced. The OMA1-DELE1-HRI pathway therefore represents a potential therapeutic target that could enable fine-tuning of the integrated stress response for beneficial outcomes in diseases that involve mitochondrial dysfunction.

DOI: https://doi.org/10.1038/s41586-020-2078-2
Int Rev Cell Mol Biol. 2020 ;pii: S1937-6448(20)30004-6. [Epub ahead of print]350 29-61

Emerging roles of the unfolded protein response (UPR) in the nervous system: A link with adaptive behavior to environmental stress?

Mei-Li Díaz-Hung, Gabriela Martínez, Claudio Hetz.

  Stressors elicit a neuroendocrine response leading to increased levels of glucocorticoids, allowing the organism to adapt to environmental changes and maintain homeostasis. Glucocorticoids have a broad effect in the body, modifying the activity of the immune system, metabolism, and behavior through the activation of receptors in the limbic system. Chronic exposition to stressors operates as a risk factor for psychiatric diseases such as depression and posttraumatic stress disorder. Among the cellular alterations observed as a consequence of environmental stress, alterations to organelle function at the level of mitochondria and endoplasmic reticulum (ER) are emerging as possible factors contributing to neuronal dysfunction. ER proteostasis alterations elicit the unfolded protein response (UPR), a conserved signaling network that re-establish protein homeostasis. In addition, in the context of brain function, the UPR has been associated to neurodevelopment, synaptic plasticity and neuronal connectivity. Recent studies suggest a role of the UPR in the adaptive behavior to stress, suggesting a mechanistic link between environmental and cellular stress. Here, we revise recent evidence supporting an evolutionary connection between the neuroendocrine system and the UPR to modulate behavioral adaptive responses.

Keywords:  Endoplasmic reticulum; Environmental stress; Glucocorticoids; Proteostasis; Unfolded protein response

DOI:  https://doi.org/10.1016/bs.ircmb.2020.01.004
Cell Death Discov. 2020 ;6 8

Delivery of phosphatidylethanolamine blunts stress in hepatoma cells exposed to elevated palmitate by targeting the endoplasmic reticulum.

Marcus Trentzsch, Eugene Nyamugenda, Tiffany K Miles, Haven Griffin, Susan Russell, Brian Koss, Kimberly A Cooney, Kevin D Phelan, Alan J Tackett, Srividhya Iyer, Gunnar Boysen, Giulia Baldini.

  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.

Keywords:  Apoptosis; Cell death

DOI:  https://doi.org/10.1038/s41420-020-0241-z