Foxp3 Post-translational Modifications and Treg Suppressive Activity

Abstract

Regulatory T cells (Tregs) are engaged in maintaining immune homeostasis and preventing autoimmunity. Treg cells include thymic Treg cells and peripheral Treg cells, both of which can suppress the immune response via multiple distinct mechanisms. The differentiation, proliferation, suppressive function and survival of Treg cells are affected by distinct energy metabolic programs. Tissue-resident Treg cells hold unique features in comparison with the lymphoid organ Treg cells. Foxp3 transcription factor is a lineage master regulator for Treg cell development and suppressive activity. Accumulating evidence indicates that the activity of Foxp3 protein is modulated by various post-translational modifications (PTMs), including phosphorylation, O-GlcNAcylation, acetylation, ubiquitylation and methylation. These modifications affect multiple aspects of Foxp3 function. In this review, we define features of Treg cells and roles of Foxp3 in Treg biology, and summarize current research in PTMs of Foxp3 protein involved in modulating Treg function. This review also attempts to define Foxp3 dimer modifications relevant to mediating Foxp3 activity and Treg suppression. Understanding Foxp3 protein features and modulation mechanisms may help in the design of rational therapies for immune diseases and cancer.

Keywords: Foxp3; O-GlcNAcylation; acetylation; methylation; phosphorylation; post-translational modification; regulatory T cells; ubiquitylation.

Figure 1

Post-translational modifications of Foxp3 and their roles in Treg suppression. A schematic representation shows the Foxp3 protein structure domains and post-translational modification sites (top). The table lists the kind of modification, modified sites, modifier enzymes, and roles in Treg suppression (bottom) (Guoping Deng and Mark I. Greene).

Figure 2

Structure model of acetylation at FOXP3 K252 downregulating suppression by destabilizing homodimerization. FOXP3 forms dynamic homodimer via zinc-finger and leucine-zipper domains, which featured as a two-stranded, anti-parallel a-helical coiled-coil. The inter-subunit hydrogen bond formed between Q234 and E248 stabilizes FOXP3 dimer via electrostatic interactions. The Q234-E248 hydrogen bond depends on the unique conformation of the E248 side chain held by K252 residue (left). Acetylation of K252 by p300 neutralizes the positive charges of K252 side chain and decreases its interaction with E248, and as a consequence, breaks the Q234-E248 inter-subunit hydrogen bond. E248-L241 and Q234-M255 form the steric tension to relax and destabilize the FOXP3 homodimerization (right). (Xiaomin Song, Guoping Deng, and Mark I. Greene).