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.
Highlights
Protein acetylation is a tightly controlled process reciprocally regulated by lysine acetyl transferases (KATs; known as histone acetyl transferases) and lysine deacetylases (KDACs; known as histone deacetylases)
Foxp3 has been reported to associate with the KATs TIP60 and p300 [5;6], while TIP60 and p300 both promote Foxp3 acetylation resulting in both increased Foxp3 protein stability and chromatin binding [5,6,7]
We demonstrate that SIRT1, but not SIRTs 2–7, co-localizes with Foxp3 in the nucleus and negatively regulates Foxp3 protein levels
Summary
Protein acetylation is a tightly controlled process reciprocally regulated by lysine acetyl transferases (KATs; known as histone acetyl transferases) and lysine deacetylases (KDACs; known as histone deacetylases). Foxp has been reported to associate with the KATs TIP60 and p300 [5;6], while TIP60 and p300 both promote Foxp acetylation resulting in both increased Foxp protein stability and chromatin binding [5,6,7]. The KDACs: HDAC1, HDAC7, HDAC9 and SIRT1 have all been reported to associate with Foxp3 They have all been shown to impair Foxp transcriptional activity or decrease protein stability, none of these KDACs have been reported to directly reduce Foxp acetylation [5;6;8]. Very recently it has been shown that Foxp protein levels were increased in SIRT1 knock-out Treg resulting in increased suppressive capacity [9]. The molecular mechanisms underlying these observations or the specificity between SIRT family members have not yet been evaluated
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