An integrated stress response regulates amino acid metabolism and resistance to oxidative stress

Mol Cell. 2003 Mar;11(3):619-33. doi: 10.1016/s1097-2765(03)00105-9.


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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Activating Transcription Factor 4
  • Amino Acids / metabolism*
  • Animals
  • Anti-Bacterial Agents / pharmacology
  • Blotting, Northern
  • Caenorhabditis elegans
  • Cell Division
  • Cell Separation
  • Cytochrome c Group / metabolism
  • Dose-Response Relationship, Drug
  • Endoplasmic Reticulum / metabolism
  • Eukaryotic Initiation Factor-2 / chemistry
  • Eukaryotic Initiation Factor-2 / metabolism*
  • Fibroblasts / metabolism
  • Flow Cytometry
  • Genotype
  • Glutathione / metabolism
  • Immunoblotting
  • Mice
  • Microscopy, Fluorescence
  • Mutation
  • Oxidative Stress*
  • Peroxidase / metabolism
  • Phosphorylation
  • Precipitin Tests
  • Time Factors
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Tunicamycin / pharmacology
  • Up-Regulation


  • Amino Acids
  • Anti-Bacterial Agents
  • Cytochrome c Group
  • Eukaryotic Initiation Factor-2
  • Transcription Factors
  • Tunicamycin
  • Activating Transcription Factor 4
  • Peroxidase
  • Glutathione