ER-stress-induced transcriptional regulation increases protein synthesis leading to cell death.
Nat Cell Biol, 2013/5;15(5):481-90.
Han J[1], Back SH, Hur J, Lin YH, Gildersleeve R, Shan J, Yuan CL, Krokowski D, Wang S, Hatzoglou M, Kilberg MS, Sartor MA, Kaufman RJ
Affiliations
PMID: 23624402DOI: 10.1038/ncb2738
Impact factor: 28.213
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.
MeSH terms
Activating Transcription Factor 4; Adenosine Triphosphate; Animals; Binding Sites; Cell Death; Cell Survival; Chromatin Immunoprecipitation; Endoplasmic Reticulum Stress; Eukaryotic Initiation Factor-2; Gene Expression Regulation; Mice; Phosphorylation; Promoter Regions, Genetic; Protein Binding; Protein Biosynthesis; Protein Folding; Protein Interaction Mapping; RNA, Messenger; Reactive Oxygen Species; Transcription Factor CHOP; Transcription, Genetic; Unfolded Protein Response
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