Inflammatory stimuli induce inhibitory S-nitrosylation of the deacetylase SIRT1 to increase acetylation and activation of p53 and p65.

Journal Article (Journal Article)

Inflammation increases the abundance of inducible nitric oxide synthase (iNOS), leading to enhanced production of nitric oxide (NO), which can modify proteins by S-nitrosylation. Enhanced NO production increases the activities of the transcription factors p53 and nuclear factor κB (NF-κB) in several models of disease-associated inflammation. S-nitrosylation inhibits the activity of the protein deacetylase SIRT1. SIRT1 limits apoptosis and inflammation by deacetylating p53 and p65 (also known as RelA), a subunit of NF-κB. We showed in multiple cultured mammalian cell lines that NO donors or inflammatory stimuli induced S-nitrosylation of SIRT1 within CXXC motifs, which inhibited SIRT1 by disrupting its ability to bind zinc. Inhibition of SIRT1 reduced deacetylation and promoted activation of p53 and p65, leading to apoptosis and increased expression of proinflammatory genes. In rodent models of systemic inflammation, Parkinson's disease, or aging-related muscular atrophy, S-nitrosylation of SIRT1 correlated with increased acetylation of p53 and p65 and activation of p53 and NF-κB target genes, suggesting that S-nitrosylation of SIRT1 may represent a proinflammatory switch common to many diseases and aging.

Full Text

Duke Authors

Cited Authors

  • Shinozaki, S; Chang, K; Sakai, M; Shimizu, N; Yamada, M; Tanaka, T; Nakazawa, H; Ichinose, F; Yamada, Y; Ishigami, A; Ito, H; Ouchi, Y; Starr, ME; Saito, H; Shimokado, K; Stamler, JS; Kaneki, M

Published Date

  • November 11, 2014

Published In

Volume / Issue

  • 7 / 351

Start / End Page

  • ra106 -

PubMed ID

  • 25389371

Pubmed Central ID

  • 25389371

Electronic International Standard Serial Number (EISSN)

  • 1937-9145

Digital Object Identifier (DOI)

  • 10.1126/scisignal.2005375


  • eng

Conference Location

  • United States