RT Journal Article
SR Electronic
T1 Inflammatory stimuli induce inhibitory S-nitrosylation of the deacetylase SIRT1 to increase acetylation and activation of p53 and p65
JF Science Signaling
JO Sci. Signal.
FD American Association for the Advancement of Science
SP ra106
OP ra106
DO 10.1126/scisignal.2005375
VO 7
IS 351
A1 Shinozaki, Shohei
A1 Chang, Kyungho
A1 Sakai, Michihiro
A1 Shimizu, Nobuyuki
A1 Yamada, Marina
A1 Tanaka, Tomokazu
A1 Nakazawa, Harumasa
A1 Ichinose, Fumito
A1 Yamada, Yoshitsugu
A1 Ishigami, Akihito
A1 Ito, Hideki
A1 Ouchi, Yasuyoshi
A1 Starr, Marlene E.
A1 Saito, Hiroshi
A1 Shimokado, Kentaro
A1 Stamler, Jonathan S.
A1 Kaneki, Masao
YR 2014
UL http://stke.sciencemag.org/content/7/351/ra106.abstract
AB 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.