Division of Nephrology, Department of Pediatrics, The Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, USA.
Curr Opin Immunol. 2011 Oct;23(5):670-8. doi: 10.1016/j.coi.2011.07.002. Epub 2011 Jul 26.
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.
赖氨酸ɛ-乙酰化是一种翻译后修饰，可改变许多蛋白质的生化特性。该反应由组蛋白/蛋白乙酰转移酶（HATs）催化，并由组蛋白/蛋白去乙酰化酶（HDACs）逆转。因此，HATs 和 HDACs 构成了一组重要的、但尚未被充分认识的蛋白质，它们控制 T 调节（Treg）细胞的功能。靶向某些 HDAC，特别是 HDAC6、HDAC9 和 Sirtuin-1（Sirt1），可以通过几种不同的、潜在的累加机制增强 Treg 的抑制效力。这些机制涉及促进叉头框 p3（Foxp3）基因表达和维持 Foxp3 赖氨酸ɛ-乙酰化，这意味着对泛素化和蛋白酶体降解具有抗性，并增加 DNA 结合。此外，消耗某些 HDAC 可以增强热休克反应，从而提高 Treg 在应激下的生存能力，并有助于维持抑制表型。因此，HDAC 抑制剂治疗可用于增强体内 Treg 功能，并对同种异体移植物存活和自身免疫性疾病产生有益影响。
