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