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

Shohei Shinozaki, Kyungho Chang, Michihiro Sakai, Nobuyuki Shimizu, Marina Yamada, Tomokazu Tanaka, Harumasa Nakazawa, Fumito Ichinose, Yoshitsugu Yamada, Akihito Ishigami, Hideki Ito, Yasuyoshi Ouchi, Marlene E. Starr, Hiroshi Saito, Kentaro Shimokado, Jonathan S. Stamler, Masao Kaneki

Research output: Contribution to journalArticlepeer-review

96 Scopus citations

Abstract

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.

Original languageEnglish
Article numberra106
JournalScience Signaling
Volume7
Issue number351
DOIs
StatePublished - Nov 11 2014

Bibliographical note

Publisher Copyright:
Copyright © 2014 American Association for the Advancement of Science. All Rights Reserved.

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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