ER-stress-induced transcriptional regulation increases protein synthesis leading to cell death
Jaeseok Han,Sung Hoon Back,Junguk Hur,Yu Hsuan Lin,Robert D. Gildersleeve,Jixiu Shan,Celvie L. Yuan,Dawid Krokowski,Shiyu Wang,Maria Hatzoglou,Michael S. Kilberg,Maureen A. Sartor,Randal J. Kaufman +12 more
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TLDR
It is shown that eIF2α-phosphorylation-attenuated protein synthesis, and not Atf4 mRNA translation, promotes cell survival, and suggesting that limiting protein synthesis will be therapeutic for diseases caused by protein misfolding in the ER.Abstract:
Protein misfolding in the endoplasmic reticulum (ER) leads to cell death through PERK-mediated phosphorylation of eIF2α, although the mechanism is not understood. ChIP-seq and mRNA-seq of activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP), key transcription factors downstream of p-eIF2α, demonstrated that they interact to directly induce genes encoding protein synthesis and the unfolded protein response, but not apoptosis. Forced expression of ATF4 and CHOP increased protein synthesis and caused ATP depletion, oxidative stress and cell death. The increased protein synthesis and oxidative stress were necessary signals for cell death. We show that eIF2α-phosphorylation-attenuated protein synthesis, and not Atf4 mRNA translation, promotes cell survival. These results show that transcriptional induction through ATF4 and CHOP increases protein synthesis leading to oxidative stress and cell death. The findings suggest that limiting protein synthesis will be therapeutic for diseases caused by protein misfolding in the ER.read more
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The integrated stress response.
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References
More filters
Journal ArticleDOI
Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources.
TL;DR: By following this protocol, investigators are able to gain an in-depth understanding of the biological themes in lists of genes that are enriched in genome-scale studies.
Journal ArticleDOI
The Unfolded Protein Response: From Stress Pathway to Homeostatic Regulation
Peter Walter,David Ron +1 more
TL;DR: The vast majority of proteins that a cell secretes or displays on its surface first enter the endoplasmic reticulum, where they fold and assemble, and only properly assembled proteins advance from the ER to the cell surface.
Journal ArticleDOI
The unfolded protein response: controlling cell fate decisions under ER stress and beyond
TL;DR: Insight is provided into the regulatory mechanisms and signalling crosstalk of the three branches of the UPR, which are initiated by the stress sensors protein kinase RNA-like ER kinase (PERK), inositol-requiring protein 1α (IRE1α) and activating transcription factor 6 (ATF6).
Journal ArticleDOI
Regulated Translation Initiation Controls Stress-Induced Gene Expression in Mammalian Cells
Heather P. Harding,Isabel Novoa,Yuhong Zhang,Huiqing Zeng,Ronald C. Wek,Matthieu Schapira,David Ron +6 more
TL;DR: Protein kinases that phosphorylate the alpha subunit of eukaryotic initiation factor 2 (eIF2alpha) are activated in stressed cells and negatively regulate protein synthesis, resulting in the induction of the downstream gene CHOP (GADD153).
Journal ArticleDOI
An Integrated Stress Response Regulates Amino Acid Metabolism and Resistance to Oxidative Stress
Heather P. Harding,Yuhong Zhang,Huiquing Zeng,Isabel Novoa,Phoebe D. Lu,Marcella Calfon,Navid Sadri,Chi Yun,Brian Popko,Richard S. Paules,David F. Stojdl,John C. Bell,Thore Hettmann,Jeffrey M. Leiden,David Ron +14 more
TL;DR: A signaling pathway initiated by eIF2alpha phosphorylation protects cells against metabolic consequences of ER oxidation by promoting the linked processes of amino acid sufficiency and resistance to oxidative stress.
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