Silent information regulator 2 potentiates Foxo1-mediated transcription through its deacetylase activity

Abstract

Longevity regulatory genes include the Forkhead transcription factor FOXO and the NAD-dependent histone deacetylase silent information regulator 2 (Sir2). Genetic studies demonstrate that Sir2 acts to extend lifespan in Caenorhabditis elegans upstream of DAF-16, a member of the FOXO family, in the insulin-like signaling pathway. However, the molecular mechanisms underlying the requirement of DAF-16 activity in Sir2-mediated longevity remain unknown. Here we show that reversible acetylation of Foxo1 (also known as FKHR), the mouse DAF-16 ortholog, modulates its transactivation function. cAMP-response element-binding protein (CREB)-binding protein binds and acetylates Foxo1 at the K242, K245, and K262 residues, the modification of which is involved in the attenuation of Foxo1 as a transcription factor. Conversely, Sir2 binds and deacetylates Foxo1 at residues acetylated by cAMPresponse element-binding protein-binding protein. Sir2 is recruited to insulin response sequence-containing promoter and increases the expression of manganese superoxide dismutase and p27 kip1 in a deacetylase-activity-dependent manner. Our findings establish Foxo1 as a direct and functional target for Sir2 in mammalian systems.

Deacetylation of FOXO3 by SIRT1 or SIRT2 leads to Skp2-mediated FOXO3 ubiquitination and degradation

“…Fukuoka et al (2003) reported that acetyl transferase CBP suppresses FOXO4 through acetylation, whereas Perrot and Rechler (2005) found that p300 acetylates FOXO1 and stimulates FOXO1-induced transcription. Similarly controversial are the effects of FOXO deacetylation by sirtuins, with reports of either increase or decrease of the expression of FOXO target genes (Brunet et al, 2004;Daitoku et al, 2004;Motta et al, 2004;van der Horst et al, 2004;Yang et al, 2005). So far, however, the data are consistent regarding the effect of FOXO deacetylation on FOXO DNA-binding to targeting gene promoters.…”

“…Caloric restriction stimulates the expression of both SIRT1 and SIRT2 (Cohen et al, 2004;Wang et al, 2007). SIRT1 regulates many cellular processes through deacetylation of various substrates (Verdin, 2007), including FOXO1, FOXO3 and FOXO4 (Brunet et al, 2004;Daitoku et al, 2004;Motta et al, 2004;van der Horst et al, 2004;Yang et al, 2005). The dysregulation of SIRT1 expression and activity is closely related to tumorigenesis (Kabra et al, 2009;Liu et al, 2009;Sung et al, 2010).…”

“…However, sirtuin deacetylation of FOXO factors may exhibit opposite functional consequences. Evidence exists that SIRT1 deacetylation of FOXOs leads to upregulation of the transcriptional activity of FOXO (Daitoku et al, 2004;van der Horst et al, 2004). Reports also show that SIRT1 exerts a negative impact on FOXO target gene expression (Motta et al, 2004;Yang et al, 2005).…”

Lifespan and mitochondrial control of neurodegeneration

“…In contrast, whereas antioxidant defense mechanisms are prominent in aerobic tissues such as retina and brain, cross-species comparisons show that they are either uncorrelated or negatively correlated with LSP 18 . Transgenic overexpression of antioxidant enzymes, such as superoxide dismutase, can have large effects on lifespan [35][36][37] , but naturally occurring antioxidant defenses do not readily account for differences in LSP 18 .…”

“…Both caloric restriction and many of these mutants use a common pathway involving SIRT protein deacetylases and the forkhead transcription factor family (FOXO or Daf-16), which can upregulate mitochondrial Sod2 and other antioxidant defenses and reduce apoptotic cell death 36,37 . Antioxidant defenses are therefore important influences on both cell death and longevity, but evolution seems to have favored limiting RONS production rather than increasing their destruction 18 , perhaps because RONS also have cellular signaling roles.…”