title: An integrated stress response regulates amino acid metabolism and resistance to oxidative stress.
abstract: Eukaryotic cells respond to unfolded proteins in their endoplasmic reticulum (ER stress), amino acid starvation, or oxidants by phosphorylating the alpha subunit of translation initiation factor 2 (eIF2alpha). This adaptation inhibits general protein synthesis while promoting translation and expression of the transcription factor ATF4. Atf4(-/-) cells are impaired in expressing genes involved in amino acid import, glutathione biosynthesis, and resistance to oxidative stress. Perk(-/-) cells, lacking an upstream ER stress-activated eIF2alpha kinase that activates Atf4, accumulate endogenous peroxides during ER stress, whereas interference with the ER oxidase ERO1 abrogates such accumulation. 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.
authors.affiliation: Skirball Institute, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Heather P
authors.initials: HP
authors.lastname: Harding
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Zhang
authors.forename: Huiquing
authors.initials: H
authors.lastname: Zeng
authors.forename: Isabel
authors.initials: I
authors.lastname: Novoa
authors.forename: Phoebe D
authors.initials: PD
authors.lastname: Lu
authors.forename: Marcella
authors.initials: M
authors.lastname: Calfon
authors.forename: Navid
authors.initials: N
authors.lastname: Sadri
authors.forename: Chi
authors.initials: C
authors.lastname: Yun
authors.forename: Brian
authors.initials: B
authors.lastname: Popko
authors.forename: Richard
authors.initials: R
authors.lastname: Paules
authors.forename: David F
authors.initials: DF
authors.lastname: Stojdl
authors.forename: John C
authors.initials: JC
authors.lastname: Bell
authors.forename: Thore
authors.initials: T
authors.lastname: Hettmann
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Leiden
authors.forename: David
authors.initials: D
authors.lastname: Ron
mesh_terms: D051701:Activating Transcription Factor 4; D000596:Amino Acids / Q000378:metabolism*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D015152:Blotting, Northern; D017173:Caenorhabditis elegans; D002455:Cell Division; D002469:Cell Separation; D003574:Cytochrome c Group / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004721:Endoplasmic Reticulum / Q000378:metabolism; D015852:Eukaryotic Initiation Factor-2 / Q000737:chemistry / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D005434:Flow Cytometry; D005838:Genotype; D005978:Glutathione / Q000378:metabolism; D015151:Immunoblotting; D051379:Mice; D008856:Microscopy, Fluorescence; D009154:Mutation; D018384:Oxidative Stress; D009195:Peroxidase / Q000378:metabolism; D010766:Phosphorylation; D011233:Precipitin Tests; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014415:Tunicamycin / Q000494:pharmacology; D015854:Up-Regulation
chemical_list: D000596:Amino Acids; D000900:Anti-Bacterial Agents; D003574:Cytochrome c Group; D015852:Eukaryotic Initiation Factor-2; D014157:Transcription Factors; D014415:Tunicamycin; D051701:Activating Transcription Factor 4; D009195:Peroxidase; D005978:Glutathione