title: JNK1 phosphorylates SIRT1 and promotes its enzymatic activity.
abstract: SIRT1 is a NAD-dependent deacetylase that regulates a variety of pathways including the stress protection pathway. SIRT1 deacetylates a number of protein substrates, including histones, FOXOs, PGC-1alpha, and p53, leading to cellular protection. We identified a functional interaction between cJUN N-terminal kinase (JNK1) and SIRT1 by coimmunoprecipitation of endogenous proteins. The interaction between JNK1 and SIRT1 was identified under conditions of oxidative stress and required activation of JNK1 via phosphorylation. Modulation of SIRT1 activity or protein levels using nicotinamide or RNAi did not modify JNK1 activity as measured by its ability to phosphorylate cJUN. In contrast, human SIRT1 was phosphorylated by JNK1 on three sites: Ser27, Ser47, and Thr530 and this phosphorylation of SIRT1 increased its nuclear localization and enzymatic activity. Surprisingly, JNK1 phosphorylation of SIRT1 showed substrate specificity resulting in deacetylation of histone H3, but not p53. These findings identify a mechanism for regulation of SIRT1 enzymatic activity in response to oxidative stress and shed new light on its role in the stress protection pathway.
authors.affiliation: Cardiovascular and Metabolism Disease Area, Novartis Institutes for BioMedical Research, Incorporated, Cambridge, Massachusetts, USA.
authors.forename: Nargis
authors.initials: N
authors.lastname: Nasrin
authors.forename: Virendar K
authors.initials: VK
authors.lastname: Kaushik
authors.forename: Eric
authors.initials: E
authors.lastname: Fortier
authors.forename: Daniel
authors.initials: D
authors.lastname: Wall
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Pearson
authors.forename: Rafael
authors.initials: R
authors.lastname: de Cabo
authors.forename: Laura
authors.initials: L
authors.lastname: Bordone
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation; D011485:Protein Binding; D021381:Protein Transport; D056564:Sirtuin 1 / Q000737:chemistry / Q000378:metabolism*
chemical_list: D048031:JNK Mitogen-Activated Protein Kinases; C447939:SIRT1 protein, human; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1