title: SIRT1 associates with eIF2-alpha and regulates the cellular stress response.
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 eIF2α. Loss of SIRT1 results in increased phosphorylation of eIF2α. 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 eIF2α dephosphorylation, GADD34 and CreP, suggesting a role for SIRT1 in the negative feedback regulation of eIF2α phosphorylation.
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219, USA; Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Hiyaa Singhee
authors.initials: HS
authors.lastname: Ghosh
authors.forename: Boris
authors.initials: B
authors.lastname: Reizis
authors.forename: Paul D
authors.initials: PD
authors.lastname: Robbins
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D010766:Phosphorylation; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013312:Stress, Physiological; D051742:Transcription Factor CHOP / Q000378:metabolism
chemical_list: C497249:DDIT3 protein, human; C497250:Ddit3 protein, mouse; D015852:Eukaryotic Initiation Factor-2; D051742:Transcription Factor CHOP; C447939:SIRT1 protein, human; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1