Histone Deacetylase 3 (HDAC3)-dependent Reversible Lysine Acetylation of Cardiac Myosin Heavy Chain Isoforms Modulates Their Enzymatic and Motor Activity

• Published in: The Journal of biological chemistry Vol. 290; no. 25; pp. 15559 - 15569
• Main Authors: Samant, Sadhana A., Pillai, Vinodkumar B., Sundaresan, Nagalingam R., Shroff, Sanjeev G., Gupta, Mahesh P.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 19.06.2015; American Society for Biochemistry and Molecular Biology
• Subjects: Acetylation; Animals; cardiac hypertrophy; Cardiomegaly - enzymology; Cardiomegaly - pathology; Cardiomegaly - physiopathology; Histone Deacetylases - metabolism; Isoenzymes - genetics; Isoenzymes - metabolism; Male; Mice; molecular cell biology; molecular motor; Myocardial Contraction; Myocardium - enzymology; Myocardium - pathology; myosin; Myosin Heavy Chains - metabolism; Sarcomeres - enzymology; Sarcomeres - pathology; Signal Transduction; myosin; molecular cell biology; cardiac hypertrophy; signal transduction; molecular motor
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M115.653048

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 α- and β-MHC isoforms were found to be reversibly acetylated. Biomechanical studies revealed that lysine acetylation significantly decreased the Km 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 α-myosin by 20% and β-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. Reversible lysine acetylation has emerged as an important post-translational modification regulating activity of the target protein. Upon lysine acetylation, enzymatic activity of both cardiac myosin heavy chain (MHC) isoforms is up-regulated. As an early response to stress, cardiac MHCs are acetylated. Contractile performance of the heart can be improved by regulating MHC acetylation without isoform switch.