Silent information regulator 2 potentiates Foxo1-mediated transcription through its deacetylase activity.
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 cAMP-response 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.
Daitoku
Hiroaki
H
Center for Tsukuba Advanced Research Alliance, University of Tsukuba, 1-1-1 Ten-noudai, Tsukuba, Ibaraki 305-8577, Japan.
Hatta
Mitsutoki
M
Matsuzaki
Hitomi
H
Aratani
Satoko
S
Ohshima
Takayuki
T
Miyagishi
Makoto
M
Nakajima
Toshihiro
T
Fukamizu
Akiyoshi
A
D000107:Acetylation; D000818:Animals; D050882:CREB-Binding Protein; D031204:Caloric Restriction; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D005786:Gene Expression Regulation; D006801:Humans; D008136:Longevity; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism; D037761:Sirtuins / Q000502:physiology*; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000502:physiology*; D014158:Transcription, Genetic; D015854:Up-Regulation
D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D009687:Nuclear Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D050882:CREB-Binding Protein; C494363:CREBBP protein, human; C494364:Crebbp protein, mouse; D037761:Sirtuins