title: Histone/protein deacetylases control Foxp3 expression and the heat shock response of T-regulatory cells.
abstract: 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.
authors.affiliation: Division of Nephrology, Department of Pediatrics, The Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, USA.
authors.forename: Ulf H
authors.initials: UH
authors.lastname: Beier
authors.forename: Tatiana
authors.initials: T
authors.lastname: Akimova
authors.forename: Yujie
authors.initials: Y
authors.lastname: Liu
authors.forename: Liqing
authors.initials: L
authors.lastname: Wang
authors.forename: Wayne W
authors.initials: WW
authors.lastname: Hancock
mesh_terms: D000107:Acetylation; D056704:Adaptive Immunity; D000818:Animals; D001327:Autoimmune Diseases / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology*; D005786:Gene Expression Regulation / Q000276:immunology; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control*; D018869:Heat-Shock Response / Q000276:immunology; D051548:Histone Acetyltransferases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D006655:Histone Deacetylases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D051379:Mice; D016377:Organ Transplantation; D011499:Protein Processing, Post-Translational / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology*; D054875:Ubiquitination
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D056572:Histone Deacetylase Inhibitors; D051548:Histone Acetyltransferases; D006655:Histone Deacetylases