Inflammatory stimuli induce inhibitory S-nitrosylation of the deacetylase SIRT1 to increase acetylation and activation of p53 and p65.
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.
Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Shriners Hospitals for Children, Harvard Medical School, Charlestown, MA 02129, USA. Department of Geriatrics and Vascular Medicine, Tokyo Medical and Dental University Graduate School, Tokyo 113-8519, Japan.
Shohei
S
Shinozaki
Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Shriners Hospitals for Children, Harvard Medical School, Charlestown, MA 02129, USA. Department of Anesthesiology and Pain Relief Center, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan.
Kyungho
K
Chang
Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Shriners Hospitals for Children, Harvard Medical School, Charlestown, MA 02129, USA.
Michihiro
M
Sakai
Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Shriners Hospitals for Children, Harvard Medical School, Charlestown, MA 02129, USA.
Nobuyuki
N
Shimizu
Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Shriners Hospitals for Children, Harvard Medical School, Charlestown, MA 02129, USA.
Marina
M
Yamada
Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Shriners Hospitals for Children, Harvard Medical School, Charlestown, MA 02129, USA.
Tomokazu
T
Tanaka
Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Shriners Hospitals for Children, Harvard Medical School, Charlestown, MA 02129, USA.
Harumasa
H
Nakazawa
Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Shriners Hospitals for Children, Harvard Medical School, Charlestown, MA 02129, USA.
Fumito
F
Ichinose
Department of Anesthesiology and Pain Relief Center, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan.
Yoshitsugu
Y
Yamada
Tokyo Metropolitan Institute of Gerontology, Tokyo 173-0015, Japan.
Akihito
A
Ishigami
Tokyo Metropolitan Institute of Gerontology, Tokyo 173-0015, Japan.
Hideki
H
Ito
Department of Geriatric Medicine, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan. Federation of National Public Service Personnel Mutual Aid Associations Toranomon Hospital, Tokyo 105-0001, Japan.
Yasuyoshi
Y
Ouchi
Department of Surgery, University of Kentucky College of Medicine, Lexington, KY 40536, USA.
Marlene E
ME
Starr
Department of Surgery, University of Kentucky College of Medicine, Lexington, KY 40536, USA.
Hiroshi
H
Saito
Department of Geriatrics and Vascular Medicine, Tokyo Medical and Dental University Graduate School, Tokyo 113-8519, Japan.
Kentaro
K
Shimokado
Institute for Transformative Molecular Medicine and Harrington Discovery Institute, Case Western Reserve University and University Hospital, Cleveland, OH 44106, USA.
Jonathan S
JS
Stamler
Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Shriners Hospitals for Children, Harvard Medical School, Charlestown, MA 02129, USA. mkaneki@helix.mgh.harvard.edu.
Masao
M
Kaneki
D000107:Acetylation; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D019556:COS Cells; D002522:Chlorocebus aethiops; D004195:Disease Models, Animal; D006801:Humans; D007249:Inflammation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D009584:Nitrogen / Q000737:chemistry*; D018384:Oxidative Stress; D051381:Rats; D011916:Rats, Inbred F344; D017386:Sequence Homology, Amino Acid; D056564:Sirtuin 1 / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D016328:NF-kappa B; C498143:RELA protein, human; C498144:Rela protein, mouse; C498145:Rela protein, rat; C495901:TP53 protein, human; D051996:Transcription Factor RelA; D016159:Tumor Suppressor Protein p53; C447939:SIRT1 protein, human; C470545:Sirt1 protein, mouse; C488368:Sirt1 protein, rat; D056564:Sirtuin 1; D009584:Nitrogen