Regulation of Treg functionality by acetylation-mediated Foxp3 protein stabilization

Abstract

Regulatory T cells (Tregs) are a specific subset of lymphocytes that are critical for the maintenance of self-tolerance. Expression levels of the transcription factor Foxp3 have been causally associated with Treg differentiation and function. Recent studies show that Foxp3 can also be transiently expressed in effector T cells; however, stable Foxp3 expression is required for development of a functional Treg suppressor phenotype. Here, we demonstrate that Foxp3 is acetylated, and this can be reciprocally regulated by the histone acetyltransferase p300 and the histone deacetylase SIRT1. Hyperacetylation of Foxp3 prevented polyubiquitination and proteasomal degradation, therefore dramatically increasing stable Foxp3 protein levels. Moreover, using mouse splenocytes, human peripheral blood mononuclear cells, T cell clones, and skin-derived T cells, we demonstrate that treatment with histone deacetylase inhibitors resulted in significantly increased numbers of functional Treg cells. Taken together, our data demonstrate that modulation of the acetylation state of Foxp3 provides a novel molecular mechanism for assuring rapid temporal control of Foxp3 levels in T cells, thereby regulating Treg numbers and functionality. Manipulating Foxp3 acetylation levels could therefore provide a new therapeutic strategy to control inappropriate (auto)immune responses.

Syntenin-mediated regulation of Sox4 proteasomal degradation modulates transcriptional output

“…Quantitative reverse transcriptase PCR RNA isolation, cDNA synthesis and quantitative PCR was performed as described (van Loosdregt et al, 2010). Forward Sox4 primer consisted of 5 0 -ggcctcgagctgggaatcgc-3 0 , reverse Sox4: 5 0 -gcccactcggggtcttgcac-3 0 ; forward syntenin: 5 0 -gcggcga gcggttccttgt-3 0 , reverse syntenin: 5 0 -tgctggattggcagggtttgcag-3 0 , b-2-microglobulin primers have been described (van Loosdregt et al, 2010).…”

“…Forward Sox4 primer consisted of 5 0 -ggcctcgagctgggaatcgc-3 0 , reverse Sox4: 5 0 -gcccactcggggtcttgcac-3 0 ; forward syntenin: 5 0 -gcggcga gcggttccttgt-3 0 , reverse syntenin: 5 0 -tgctggattggcagggtttgcag-3 0 , b-2-microglobulin primers have been described (van Loosdregt et al, 2010).…”

Sirtuins and inflammation: Friends or foes?

“…SIRT1 has been shown to bind and decrease FoxP3 protein levels, possibly through its deacetylation. Accordingly, nicotinamide mediated SIRT1 inhibition increases both FoxP3 + protein levels and the relative proportion of FoxP3+ cells, resulting in an overall increased Treg suppressive function [42]. In line with these results, Yang and coworkers reported that resveratrol, a natural SIRT1 activator [43], depletes CD4 + CD25 + Tregs in tumor-bearing mice [44].…”

“…Noteworthy, sirtuin activity has been shown to play a role in related processes such as cellular and organismal lifespan extension [6], [7], glucose homeostasis [63] and cellular differentiation [42], [58]. The work reviewed herein suggests that some of the pathological processes linked to metabolic disorders or aging may in fact be functionally linked to the immunomodulatory function of this family of metabolic sensors.…”

“…High and stable levels of FoxP3 expression have been proposed to be required for adequate Treg function [41]. The acetylated form of FoxP3 displays improved repressive functions and is a poor substrate for polyubiquitinmediated degradation [42]. SIRT1 has been shown to bind and decrease FoxP3 protein levels, possibly through its deacetylation.…”