Histone/protein deacetylases control Foxp3 expression and the heat shock response of T-regulatory cells

Lysine ɛ-acetylation is a post-translational modification that alters the biochemical properties of many proteins. The reaction is catalyzed by histone/protein acetyltransferases (HATs), and is reversed by histone/protein deacetylases (HDACs). As a result, HATs and HDACs constitute an important, though little recognized, set of proteins that control the functions of T-regulatory (Treg) cells. Targeting certain HDACs, especially HDAC6, HDAC9, and Sirtuin-1 (Sirt1), can augment Treg suppressive potency by several distinct and potentially additive mechanisms. These involve promoting Forkhead box p3 (Foxp3) gene expression and preserving Foxp3 lysine ɛ-acetylation, which infers resistance to ubiquitination and proteasomal degradation, and increases DNA binding. Moreover, depleting certain HDAC can enhance the heat shock response, which increases the tenacity of Treg to survive under stress, and helps preserve a suppressive phenotype. As a result, HDAC inhibitor therapy can be used to enhance Treg functions in vivo and have beneficial effects on allograft survival and autoimmune diseases.

► HATs and HDACs control lysine acetylation, an important post-translational modification in histone and non-histone proteins. ► Acetylation of Foxp3 in Tregs increases both its DNA binding and resistance to proteasomal degradation. ► Foxp3 transcription factors are regulated by acetylation (p65, STAT5) or indirectly by HDAC/HAT dependent mediators (SMAD3). ► Targeting HDAC6 or HDAC9 increases HSR gene expression which protects Treg from stress and preserves a suppressive phenotype.