SIRT1 functionally interacts with the metabolic regulator and transcriptional coactivator PGC-1{alpha}.
In lower organisms, increased expression of the NAD-dependent deacetylase Sir2 augments lifespan. The mechanism through which this life extension is mediated remains incompletely understood. Here we have examined the cellular effects of overexpression of SIRT1, the closest mammalian ortholog of Sir2. In PC12 cells, increased expression of the NAD-dependent deacetylase SIRT1 reduces cellular oxygen consumption by approximately 25%. We further demonstrate that SIRT1 expression can alter the transcriptional activity of the mitochondrial biogenesis coactivator PGC-1alpha. In addition, SIRT1 and PGC-1alpha directly interact and can be co-immunoprecipitated as a molecular complex. A single amino acid mutation in the putative ADP-ribosyltransferase domain of SIRT1 inhibits the interaction of SIRT1 with PGC-1alpha but does not effect the interaction of SIRT1 with either p53 or Foxo3a. We further show that PGC-1alpha is acetylated in vivo. This acetylation is augmented by treatment with the SIRT1 inhibitor nicotinamide or by expression of the transcriptional coactivator p300. Finally we demonstrate that SIRT1 catalyzes PGC-1alpha deacetylation both in vitro and in vivo. These results provide a direct link between the sirtuins, a family of proteins linked to lifespan determination and PGC-1alpha, a coactivator that regulates cellular metabolism.
Nemoto
Shino
S
Cardiovascular Branch, NHLBI, National Institutes of Health, Bethesda, Maryland 20892-1454, USA.
Fergusson
Maria M
MM
Finkel
Toren
T
D000107:Acetylation; D000818:Animals; D004268:DNA-Binding Proteins / Q000378:metabolism; D050881:E1A-Associated p300 Protein; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D006367:HeLa Cells; D006801:Humans; D009243:NAD / Q000378:metabolism; D009419:Nerve Tissue Proteins; D009536:Niacinamide / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D010101:Oxygen Consumption / Q000502:physiology; D016716:PC12 Cells; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D056564:Sirtuin 1; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D004268:DNA-Binding Proteins; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C501429:Ppargc1a protein, rat; D016601:RNA-Binding Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D009243:NAD; C074639:Foxo1 protein, rat; D009536:Niacinamide; D050881:E1A-Associated p300 Protein; C494362:Ep300 protein, rat; C488368:Sirt1 protein, rat; D056564:Sirtuin 1; D037761:Sirtuins