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

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.

• Authors: 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
• Journal: Science signaling (Sci Signal) Vol. 7 Issue 351 Pg. ra106 (Nov 11 2014) ISSN: 1937-9145 [Electronic] United States
• PMID: 25389371 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014, American Association for the Advancement of Science.

Chemical References

• NF-kappa B
• RELA protein, human
• Rela protein, mouse
• Rela protein, rat
• TP53 protein, human
• Transcription Factor RelA
• Tumor Suppressor Protein p53
• SIRT1 protein, human
• Sirt1 protein, mouse
• Sirt1 protein, rat
• Sirtuin 1
• Nitrogen

Topics

• Acetylation
• Amino Acid Motifs
• Amino Acid Sequence
• Animals
• Apoptosis
• COS Cells
• Chlorocebus aethiops
• Disease Models, Animal
• Humans
• Inflammation
• Male
• Mice
• Mice, Inbred C57BL
• Molecular Sequence Data
• NF-kappa B (metabolism)
• Nitrogen (chemistry)
• Oxidative Stress
• Rats
• Rats, Inbred F344
• Sequence Homology, Amino Acid
• Sirtuin 1 (metabolism)
• Transcription Factor RelA (metabolism)
• Tumor Suppressor Protein p53 (metabolism)