Cited by 1,691Endoplasmic Reticulum Stress and DiseaseHeat shock proteins researchIon Channels and Receptors

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ER-stress-induced transcriptional regulation increases protein synthesis leading to cell death

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Han, Jaeseok, Back, Sung Hoon, Hur, Junguk, Lin, Yu-Hsuan, Gildersleeve, Robert, Shan, Jixiu, Yuan, Celvie L., Krokowski, Dawid, Wang, Shiyu, Hatzoglou, Maria, Kilberg, Michael S., Sartor, Maureen A., Kaufman, Randal J.·2013·Nature Cell Biology

DOI 10.1038/ncb2738PMC PMC3692270

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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.

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Authors: Han, J., Back, S. H., Hur, J., Lin, Y.-H., Gildersleeve, R., Shan, J., Yuan, C. L., Krokowski, D., Wang, S., Hatzoglou, M., Kilberg, M. S., Sartor, M. A., & Kaufman, R. J.
Affiliations: Sanford Burnham Prebys Medical Discovery Institute (US)
University of Michigan (US)
University of Florida (US)
Case Western Reserve University (US)
Corresponding author: Kaufman, Randal J.
ORCID: Han, Jaeseok
Back, Sung Hoon
Hur, Junguk
Lin, Yu-Hsuan
Shan, Jixiu
Krokowski, Dawid
Wang, Shiyu
Hatzoglou, Maria
Sartor, Maureen A.
Kaufman, Randal J.
Venue: Nature Cell Biology
Publisher: Springer Science and Business Media LLC
Published: 2013-04-28
Volume: 15
Issue: 5
Pages: 481-490
ISSN: 1465-7392 (ISSN-L)
1476-4679
DOI: 10.1038/ncb2738
PMC: PMC3692270
OpenAlex: W2074471441
Cited by: 1,691
References: 66
Citations by year: 2026: 102 · 2025: 136 · 2024: 140 · 2023: 136 · 2022: 153 · 2021: 136 · 2020: 153 · 2019: 123 · 2018: 127 · 2017: 118 · 2016: 117 · 2015: 112 · 2014: 102 · 2013: 30
FWCI: 70.01
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springer.com/tdm (tdm)
Locations: Nature Cell Biology (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: University of Michigan
National Heart, Lung, and Blood Institute (R01HL052173, HL 057346, P01HL057346, HL052173)
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK088227, R01DK042394, R24DK093074, DK-042394, R01DK094729, DK092062, DK53307, DK088227, DK-094729, R01DK053307, DK60596, DK093074, R37DK060596, R01DK092062, R37DK042394, R01DK060596)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
Keywords: endoplasmic reticulum stress, unfolded protein response, ATF4, CHOP, eIF2α phosphorylation, protein synthesis, oxidative stress, ATP depletion, cell death, transcriptional regulation, protein misfolding, apoptosis
MeSH terms: Adenosine Triphosphate, Animals, Binding Sites, Cell Survival, Gene Expression Regulation, Phosphorylation, Promoter Regions, Genetic, Protein Binding, RNA, Messenger, Transcription, Genetic, Protein Biosynthesis, Eukaryotic Initiation Factor-2, Cell Death, Reactive Oxygen Species, Protein Folding, Protein Interaction Mapping, Chromatin Immunoprecipitation, Mice, Activating Transcription Factor 4, Transcription Factor CHOP, Unfolded Protein Response, Endoplasmic Reticulum Stress

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ER-stress-induced transcriptional regulation increases protein synthesis leading to cell death

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