title: Rapid temporal control of Foxp3 protein degradation by sirtuin-1.
abstract: Maintenance of Foxp3 protein expression in regulatory T cells (Treg) is crucial for a balanced immune response. We have previously demonstrated that Foxp3 protein stability can be regulated through acetylation, however the specific mechanisms underlying this observation remain unclear. Here we demonstrate that SIRT1 a member of the lysine deacetylase Sirtuin (SIRT) family, but not the related SIRTs 2-7, co-localize with Foxp3 in the nucleus. Ectopic expression of SIRT1, but not SIRTs 2-7 results in decreased Foxp3 acetylation, while conversely inhibition of endogenous SIRT activity increased Foxp3 acetylation. We show that SIRT1 inhibition decreases Foxp3 poly-ubiquitination, thereby increasing Foxp3 protein levels. Co-transfection of SIRT1 with Foxp3 results in increased Foxp3 proteasomal degradation, while SIRT inhibition increases FOXP3 transcriptional activity in human Treg. Taken together, these data support a central role for SIRT1 in the regulation of Foxp3 protein levels and thereby in regulation of Treg suppressive capacity. Pharmacological modulation of SIRT1 activity in Treg may therefore provide a novel therapeutic strategy for controlling immune responses.
authors.affiliation: Department of Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Jorg
authors.initials: J
authors.lastname: van Loosdregt
authors.forename: Diede
authors.initials: D
authors.lastname: Brunen
authors.forename: Veerle
authors.initials: V
authors.lastname: Fleskens
authors.forename: Cornelieke E G M
authors.initials: CE
authors.lastname: Pals
authors.forename: Eric W F
authors.initials: EW
authors.lastname: Lam
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Coffer
mesh_terms: D000107:Acetylation; D015153:Blotting, Western; D002460:Cell Line; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D006801:Humans; D006868:Hydrolysis; D047468:Immunoprecipitation; D007700:Kinetics; D018613:Microscopy, Confocal; D056564:Sirtuin 1 / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism; D054875:Ubiquitination
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C447939:SIRT1 protein, human; D056564:Sirtuin 1