SIRT1 associates with eIF2-alpha and regulates the cellular stress response

Hiyaa Singhee Ghosh, Boris Reizis, Paul D. Robbins

Research output: Contribution to journalArticlepeer-review

46 Scopus citations

Abstract

SIRT1 is a NAD+ dependent protein deacetylase known to increase longevity in model organisms. SIRT1 regulates cellular response to oxidative and/or genotoxic stress by regulating proteins such as p53 and FOXO. The eukaryotic initiation factor-2, eIF2, plays a critical role in the integrated stress response pathway. Under cellular stress, phosphorylation of the alpha subunit of eIF2 is essential for immediate shut-off of translation and activation of stress response genes. Here we demonstrate that SIRT1 interacts with eIFα. Loss of SIRT1 results in increased phosphorylation of eIFα. However, the downstream stress induced signaling pathway is compromised in SIRT1-deficient cells, indicated by delayed expression of the downstream target genes CHOP and GADD34 and a slower post-stress translation recovery. Finally, SIRT1 co-immunoprecipitates with mediators of eIFα dephosphorylation, GADD34 and CreP, suggesting a role for SIRT1 in the negative feedback regulation of eIFα phosphorylation.

Original languageEnglish (US)
Article number150
JournalScientific reports
Volume1
DOIs
StatePublished - 2011
Externally publishedYes

Bibliographical note

Funding Information:
We would like to thank Daniel Knight for technical assistance. This work was supported by DOD grants 17-03-1-0488 and 17-03-0142 and NIH grants CA103730 and AR051456 to P.D.R.

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