Regulation of Acetylation of Histone Deacetylase 2 by p300/CBP-Associated Factor/Histone Deacetylase 5 in the Development of Cardiac Hypertrophy
Regulation of Acetylation of Histone Deacetylase 2 by p300/CBP-Associated Factor/Histone Deacetylase 5 in the Development of Cardiac Hypertrophy
复制标题
DOI：
10.1161/circresaha.114.303429
复制
发表时间：
2014-03-28
影响因子：
20.1
通讯作者：
Kook, Hyun
中科院分区：
文献类型：
--
作者：
Eom, Gwang Hyeon;Nam, Yoon Seok;Kook, Hyun
基本原理：组蛋白脱乙酰酶（HDAC）与心脏重编程密切相关。虽然I类和IIa类HDACs的功能作用是公认的，类间串扰的意义，在发展中的心脏hypertrophy.Objective：最近，我们提出，酪蛋白激酶21依赖磷酸化HDAC 2导致酶激活，这反过来又诱导心肌肥厚。本文报道了HDAC 2的另一种翻译后激活机制，即p300/CBP相关因子/HDAC 5介导的HDAC 2乙酰化。方法和结果：在心肌细胞和小鼠模型中，Hdac 2在肥大应激反应中均发生乙酰化。组蛋白乙酰转移酶抑制剂可减少乙酰化作用，但非特异性HDAC抑制剂可增加乙酰化作用。Hdac 2的酶活性与其乙酰化状态呈正相关。p300/CBP相关因子与Hdac 2结合并诱导乙酰化。HDAC 2 K75残基负责肥大应激诱导的乙酰化。乙酰化抗性的Hdac 2 K75 R在S394上的磷酸化显着降低，这导致内在活性的丧失。Hdac 5，IIa类HDAC之一，直接脱乙酰化Hdac 2。在Hdac 5-null小鼠中Hdac 2的乙酰化增加。当乙酰化模拟突变体的Hdac 2感染到心肌细胞，无论是核拴系Hdac 5与链霉素B或Hdac 5过表达的抗肥大作用reduced.Conclusions：两者合计，我们的研究结果表明，HDAC 2乙酰化的平衡调节p300/CBP相关因子和HDAC 5在心肌肥厚的发展一种新的机制。
Rationale: Histone deacetylases (HDACs) are closely involved in cardiac reprogramming. Although the functional roles of class I and class IIa HDACs are well established, the significance of interclass crosstalk in the development of cardiac hypertrophy remains unclear.Objective: Recently, we suggested that casein kinase 21-dependent phosphorylation of HDAC2 leads to enzymatic activation, which in turn induces cardiac hypertrophy. Here we report an alternative post-translational activation mechanism of HDAC2 that involves acetylation of HDAC2 mediated by p300/CBP-associated factor/HDAC5.Methods and Results: Hdac2 was acetylated in response to hypertrophic stresses in both cardiomyocytes and a mouse model. Acetylation was reduced by a histone acetyltransferase inhibitor but was increased by a nonspecific HDAC inhibitor. The enzymatic activity of Hdac2 was positively correlated with its acetylation status. p300/CBP-associated factor bound to Hdac2 and induced acetylation. The HDAC2 K75 residue was responsible for hypertrophic stress-induced acetylation. The acetylation-resistant Hdac2 K75R showed a significant decrease in phosphorylation on S394, which led to the loss of intrinsic activity. Hdac5, one of class IIa HDACs, directly deacetylated Hdac2. Acetylation of Hdac2 was increased in Hdac5-null mice. When an acetylation-mimicking mutant of Hdac2 was infected into cardiomyocytes, the antihypertrophic effect of either nuclear tethering of Hdac5 with leptomycin B or Hdac5 overexpression was reduced.Conclusions: Taken together, our results suggest a novel mechanism by which the balance of HDAC2 acetylation is regulated by p300/CBP-associated factor and HDAC5 in the development of cardiac hypertrophy.