title: ER-stress-induced transcriptional regulation increases protein synthesis leading to cell death.
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.
authors.affiliation: Center for Neuroscience, Aging, and Stem Cell Research, Sanford Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Jaeseok
authors.initials: J
authors.lastname: Han
authors.forename: Sung Hoon
authors.initials: SH
authors.lastname: Back
authors.forename: Junguk
authors.initials: J
authors.lastname: Hur
authors.forename: Yu-Hsuan
authors.initials: YH
authors.lastname: Lin
authors.forename: Robert
authors.initials: R
authors.lastname: Gildersleeve
authors.forename: Jixiu
authors.initials: J
authors.lastname: Shan
authors.forename: Celvie L
authors.initials: CL
authors.lastname: Yuan
authors.forename: Dawid
authors.initials: D
authors.lastname: Krokowski
authors.forename: Shiyu
authors.initials: S
authors.lastname: Wang
authors.forename: Maria
authors.initials: M
authors.lastname: Hatzoglou
authors.forename: Michael S
authors.initials: MS
authors.lastname: Kilberg
authors.forename: Maureen A
authors.initials: MA
authors.lastname: Sartor
authors.forename: Randal J
authors.initials: RJ
authors.lastname: Kaufman
mesh_terms: D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D016923:Cell Death; D002470:Cell Survival; D047369:Chromatin Immunoprecipitation; D059865:Endoplasmic Reticulum Stress; D015852:Eukaryotic Initiation Factor-2 / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D051379:Mice; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D014176:Protein Biosynthesis; D017510:Protein Folding; D025941:Protein Interaction Mapping; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D056811:Unfolded Protein Response
chemical_list: C081452:Atf4 protein, mouse; C497250:Ddit3 protein, mouse; D015852:Eukaryotic Initiation Factor-2; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D051701:Activating Transcription Factor 4; D051742:Transcription Factor CHOP; D000255:Adenosine Triphosphate