Histone Deacetylase 3 (HDAC3)-dependent Reversible Lysine Acetylation of Cardiac Myosin Heavy Chain Isoforms Modulates Their Enzymatic and Motor Activity
Histone Deacetylase 3 (HDAC3)-dependent Reversible Lysine Acetylation of Cardiac Myosin Heavy Chain Isoforms Modulates Their Enzymatic and Motor Activity
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DOI：
10.1074/jbc.m115.653048
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发表时间：
2015-06-19
影响因子：
4.8
通讯作者：
Gupta, Mahesh P.
中科院分区：
文献类型：
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作者：
Samant, Sadhana A.;Pillai, Vinodkumar B.;Gupta, Mahesh P.
背景：可逆赖氨酸乙酰化已成为调节靶蛋白活性的重要翻译后修饰。结果：赖氨酸乙酰化后，两种心肌肌球蛋白重链 (MHC) 亚型的酶活性均上调。结论：作为对应激的早期反应，心脏 MHC 被乙酰化。意义：通过调节 MHC 乙酰化无需异构体转换即可改善心脏的收缩性能。可逆赖氨酸乙酰化是一种广泛的翻译后修饰，控制不同亚细胞区室中蛋白质的活性。我们之前证明，II 类组蛋白脱乙酰酶 (HDAC)、HDAC4 和组蛋白乙酰转移酶、p300/CREB 结合蛋白相关因子与心脏肌节相关，而 I 类和 II 类 HDAC 抑制剂曲古抑菌素 A 可以增强肌丝的收缩活性。在这项研究中，我们表明 I 类 HDAC（HDAC3）也存在于心脏肌节中。通过免疫组织化学和电子显微镜分析，我们发现 HDAC3 定位于肌节的 A 带，能够使肌球蛋白重链 (MHC) 亚型脱乙酰化。发现心脏 - 和 -MHC 亚型的运动结构域是可逆乙酰化的。生物力学研究表明，赖氨酸乙酰化显着降低了 MHC 亚型肌动蛋白激活的 ATP 酶活性的 K-m。通过体外运动测定，我们发现，与各自的非乙酰化亚型相比，赖氨酸乙酰化使β-肌球蛋白和β-肌球蛋白的肌动蛋白滑动速度增加了20%和36%。此外，发现肌球蛋白乙酰化对心脏应激敏感。在诱导肥大期间，肌球蛋白同工型乙酰化随着应激刺激的持续时间逐渐增加，与同工型转变无关，这表明肌球蛋白的赖氨酸乙酰化可能是肌丝增加心脏收缩性能的早期反应。这些研究为 HDAC3 在肌丝上的定位提供了第一个证据，并揭示了调节心脏 MHC 亚型运动活动的新机制。
Background: Reversible lysine acetylation has emerged as an important post-translational modification regulating activity of the target protein. Results: Upon lysine acetylation, enzymatic activity of both cardiac myosin heavy chain (MHC) isoforms is up-regulated. Conclusion: As an early response to stress, cardiac MHCs are acetylated. Significance: Contractile performance of the heart can be improved by regulating MHC acetylation without isoform switch.Reversible lysine acetylation is a widespread post-translational modification controlling the activity of proteins in different subcellular compartments. We previously demonstrated that a class II histone deacetylase (HDAC), HDAC4, and a histone acetyltransferase, p300/CREB-binding protein-associated factor, associate with cardiac sarcomeres and that a class I and II HDAC inhibitor, trichostatin A, enhances contractile activity of myofilaments. In this study we show that a class I HDAC, HDAC3, is also present at cardiac sarcomeres. By immunohistochemical and electron microscopic analyses, we found that HDAC3 was localized to A-band of sarcomeres and capable of deacetylating myosin heavy chain (MHC) isoforms. The motor domains of both cardiac - and -MHC isoforms were found to be reversibly acetylated. Biomechanical studies revealed that lysine acetylation significantly decreased the K-m for the actin-activated ATPase activity of MHC isoforms. By in vitro motility assay, we found that lysine acetylation increased the actin-sliding velocity of -myosin by 20% and -myosin by 36% compared with their respective non-acetylated isoforms. Moreover, myosin acetylation was found to be sensitive to cardiac stress. During induction of hypertrophy, myosin isoform acetylation increased progressively with duration of stress stimuli independently of isoform shift, suggesting that lysine acetylation of myosin could be an early response of myofilaments to increase contractile performance of the heart. These studies provide the first evidence for localization of HDAC3 at myofilaments and uncover a novel mechanism modulating the motor activity of cardiac MHC isoforms.