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ARS Home » Plains Area » Houston, Texas » Children's Nutrition Research Center » Research » Publications at this Location » Publication #230136
Title: SIRT1 and SIRT2 deacetylation of FOXO3a promotes FOXO3a ubiquitination and proteosomal degradation

Author
item WANG, FEI - BAYLOR COLLEGE MED
item Tong, Qiang

Submitted to: Meeting Abstract
Publication Type: Abstract Only
Publication Acceptance Date: 3/8/2007
Publication Date: 6/2/2007
Citation: Wang, F., Tong, Q. 2007. SIRT1 and sIRT2 deacetylation of FOXO3a promotes FOXO3a ubiquitination and proteosomal degradation [abstract]. In: FASEB Histone Deacetylase Meeting, June 2-7, 2007, Snowmass Village, Colorado. 45.

Interpretive Summary:

Technical Abstract: NAD-dependent deacetylases, Sir2 and Hst2, mediate the lifespan extension effect of caloric restriction in yeast. Whether their mammalian orthologs, SIRT1 and SIRT2, have a similar function remains unknown. It was reported that SIRT1 can be induced by caloric restriction in rodents, and SIRT1 is known to deacetylate FOXO transcription factors. We found that caloric restriction also elevates SIRT2 expression in mice and that SIRT2 binds and deacetylates FOXO3a, resulting in increased binding of FOXO3a to its target gene promoters and subsequent increase in the expression of P27(Kip1), MnSOD, and Bim. As a consequence, SIRT2 decreases cellular reactive oxygen species and promotes apoptosis. However, there are also reports showing that SIRT1 exerts a negative impact on FOXO, suggesting the possibility of additional regulatory mechanisms. Since acetylation and ubiquitination both occur in the lysine residues, it led us to study the potential role of SIRT1 and SIRT2 deacetylation in facilitating ubiquitination. In the presence of SIRT1 and SIRT2, FOXO3a poly-ubiquitination was increased while a mutant SIRT2, which lacks the deacetylase activity, abolished this effect. When protein synthesis was blocked by cycloheximide, FOXO3a protein abundance decreased faster in cells transfected with either SIRT1 or SIRT2, but not in cells expressing SRT2 deacetylase mutant. Using FOXO3a-GFP and flow cytometry, we have determined that SIRT2 reduced the half life of FOXO3a. In NIH3T3 cells stably expressing SIRT1 or SIRT2, the cellular FOXO3a level was reduced, while SIRT2 knockdown significantly elevated FOXO3a level. Proteosome inhibitor (MG-132) treatment prevented SIRT2-mediated FOXO3a degradation, indicating that this process is proteasome-dependent. Our data indicates that along with the up-regulation of FOXO transcription activity, deacetylation of FOXO3a by SIRT1 and SIRT2 also promote its poly-ubiquitination and proteasome degradation.