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Rapid temporal control of Foxp3 protein degradation by sirtuin-1.

Authors
  • van Loosdregt, Jorg1
  • Brunen, Diede
  • Fleskens, Veerle
  • Pals, Cornelieke E G M
  • Lam, Eric W F
  • Coffer, Paul J
  • 1 Department of Immunology, University Medical Center Utrecht, Utrecht, The Netherlands. , (Netherlands)
Type
Published Article
Journal
PLoS ONE
Publisher
Public Library of Science
Publication Date
Apr 20, 2011
Volume
6
Issue
4
Identifiers
DOI: 10.1371/journal.pone.0019047
PMID: 21533107
Source
Medline
Language
English
License
Unknown

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.

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