FOXO4 is acetylated upon peroxide stress and deacetylated by the longevity protein hSir2(SIRT1).
FOXO transcription factors have important roles in metabolism, cellular proliferation, stress tolerance, and aging. FOXOs are negatively regulated by protein kinase B/c-Akt-mediated phosphorylation. Here we show that FOXO factors are also subject to regulation by reversible acetylation. We provide evidence that the acetyltransferase CREB-binding protein (CBP) binds FOXO resulting in acetylation of FOXO. This acetylation inhibits FOXO transcriptional activity. Binding of CBP and acetylation are induced after treatment of cells with peroxide stress. Deacetylation of FOXOs involves binding of the NAD-dependent deacetylase hSir2(SIRT1). Accordingly, hSir2(SIRT1)-mediated deacetylation precludes FOXO inhibition through acetylation and thereby prolongs FOXO-dependent transcription of stress-regulating genes. These data demonstrate that acetylation functions in a second pathway of negative control for FOXO factors and provides a novel mechanism whereby hSir2(SIRT1) can promote cellular survival and increase lifespan.
van der Horst
Armando
A
Department of Physiological Chemistry, Center for Biomedical Genetics, University Medical Center Utrecht, 3584 CG Utrecht, The Netherlands.
Tertoolen
Leon G J
LG
de Vries-Smits
Lydia M M
LM
Frye
Roy A
RA
Medema
René H
RH
Burgering
Boudewijn M T
BM
D000107:Acetylation; D050882:CREB-Binding Protein; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D051858:Forkhead Transcription Factors; D005786:Gene Expression Regulation; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D016877:Oxidants / Q000378:metabolism*; D018384:Oxidative Stress; D011485:Protein Binding; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D056564:Sirtuin 1; D037761:Sirtuins / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
D018797:Cell Cycle Proteins; C108803:FOXO4 protein, human; D051858:Forkhead Transcription Factors; D009687:Nuclear Proteins; D016877:Oxidants; D011993:Recombinant Fusion Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D006861:Hydrogen Peroxide; D050882:CREB-Binding Protein; C494363:CREBBP protein, human; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D037761:Sirtuins; D006655:Histone Deacetylases