|Qin, F Xiao-feng|
Submitted to: Aging Cell
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/8/2007
Publication Date: 8/8/2007
Citation: Wang, F., Nguyen, M., Qin, F.X., Qiang, T. 2007. SIRT2 deacetylates FOXO3a in response to oxidative stress and caloric restriction. Aging Cell. 6(4):505-514. Interpretive Summary: Dietary caloric restriction extends animal life span. Elucidation of the underlying molecular mechanism may lead to better approaches to achieve beneficial health effects. Sirtuin proteins were found to mediate life span extension effect of caloric restriction in yeast. We explored the function of mammalian sirtuins and found the expression of one of the sirtuin protein, SIRT2, was induced by caloric restriction in mouse tissues. We also found that SIRT2 modifies (deacetylates) FOXO3a, which is a key factor regulating many cellular processes, such as anti-oxidation and cell death. We found that SIRT2 interaction with FOXO3a to increase FOXO3a binding to DNA and up-regulate its down-stream pathways. This led to decreased free radical levels and increased cell death under stress. Our findings shed light on the anti-aging function of SIRT2 and how it may mediate the effects of caloric restriction.
Technical Abstract: The sirtuin family of nicotinamide adenine dinucleotide-dependent (NAD) deacetylases plays an important role in aging and metabolic regulation. In yeast, the Sir2 gene and its homolog Hst2 independently mediate the action of caloric restriction on lifespan extension. The mammalian Sir2 ortholog, SIRT1, is up-regulated by caloric restriction and deacetylates a variety of substrates, including histones and the forkhead box O (FOXO) transcription factors. The mammalian ortholog of Hst2, SIRT2, was shown to co-localize with microtubules and functions as alpha-tubulin deacetylase. During G2/M phase, SIRT2 proteins enter nuclei and deacetylate histones. We report here that the expression of SIRT2 is elevated in the white adipose tissue and kidney of caloric-restricted mice. Oxidative stress, such as hydrogen peroxide treatment, also increases SIRT2 expression in cells. We have demonstrated that SIRT2 binds to FOXO3a and reduces its acetylation level. SIRT2 hence increases FOXO DNA binding and elevates the expression of FOXO target genes, p27(Kip1), manganese superoxide dismutase and Bim. As a consequence, SIRT2 decreases cellular levels of reactive oxygen species. Furthermore, as Bim is a pro-apoptotic factor, SIRT2 promotes cell death when cells are under severe stress. Therefore, mammalian SIRT2 responds to caloric restriction and oxidative stress to deacetylate FOXO transcription factors.