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

Heather P. Harding, Yuhong Zhang, Huiquing Zeng, Isabel Novoa, Phoebe D. Lu, Marcella Calfon, Navid Sadri, Chi Yun, Brian Popko, Richard Paules, David F. Stojdl, John C. Bell, Thore Hettmann, Jeffrey M. Leiden, David Ron*

*Corresponding author for this work

Research output: Contribution to journalArticle

1942 Scopus citations

Abstract

Eukaryotic cells respond to unfolded proteins in their endoplasmic reticulum (ER stress), amino acid starvation, or oxidants by phosphorylating the α subunit of translation initiation factor 2 (eIF2α). 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 eIF2α 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 eIF2α phosphorylation protects cells against metabolic consequences of ER oxidation by promoting the linked processes of amino acid sufficiency and resistance to oxidative stress.

Original languageEnglish (US)
Pages (from-to)619-633
Number of pages15
JournalMolecular cell
Volume11
Issue number3
DOIs
StatePublished - Mar 1 2003

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Harding, H. P., Zhang, Y., Zeng, H., Novoa, I., Lu, P. D., Calfon, M., Sadri, N., Yun, C., Popko, B., Paules, R., Stojdl, D. F., Bell, J. C., Hettmann, T., Leiden, J. M., & Ron, D. (2003). An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Molecular cell, 11(3), 619-633. https://doi.org/10.1016/S1097-2765(03)00105-9