HDAC4 and PCAF Bind to Cardiac Sarcomeres and Play a Role in Regulating Myofilament Contractile Activity

• Published in: The Journal of biological chemistry Vol. 283; no. 15; pp. 10135 - 10146
• Main Authors: Gupta, Mahesh P., Samant, Sadhana A., Smith, Stephen H., Shroff, Sanjeev G.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 11.04.2008; American Society for Biochemistry and Molecular Biology
• Subjects: Actin Cytoskeleton - genetics; Actin Cytoskeleton - metabolism; Actin Cytoskeleton - ultrastructure; Animals; Calcium - metabolism; Enzyme Inhibitors - pharmacology; Histone Deacetylase Inhibitors; Histone Deacetylases - genetics; Histone Deacetylases - metabolism; Hydroxamic Acids - pharmacology; LIM Domain Proteins; Mechanisms of Signal Transduction; Mice; Mice, Knockout; Muscle Proteins - genetics; Muscle Proteins - metabolism; Myocardial Contraction - physiology; Myocardium - enzymology; Myocardium - ultrastructure; Myocytes, Cardiac; p300-CBP Transcription Factors - genetics; p300-CBP Transcription Factors - metabolism; Rabbits; Rats; Sarcomeres - enzymology; Sarcomeres - genetics; Sarcomeres - ultrastructure; Vesicular Transport Proteins - genetics; Vesicular Transport Proteins - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M710277200

Reversible acetylation of lysine residues within a protein is considered a biologically relevant modification that rivals phosphorylation (Kouzarides, T. (2000) EMBO J. 19, 1176-1179). The enzymes responsible for such protein modification are called histone acetyltransferases (HATs) and deacetylases (HDACs). A role of protein phosphorylation in regulating muscle contraction is well established (Solaro, R. J., Moir, A. J., and Perry, S. V. (1976) Nature 262, 615-617). Here we show that reversible protein acetylation carried out by HATs and HDACs also plays a role in regulating the myofilament contractile activity. We found that a Class II HDAC, HDAC4, and an HAT, PCAF, associate with cardiac myofilaments. Primary cultures of cardiomyocytes as well as mouse heart sections examined by immunohistochemical and electron microscopic analyses revealed that both HDAC4 and PCAF associate with the Z-disc and I- and A-bands of cardiac sacromeres. Increased acetylation of sarcomeric proteins by HDAC inhibition (using class I and II HDAC inhibitors or anti-HDAC4 antibody) enhanced the myofilament calcium sensitivity. We identified the Z-disc-associated protein, MLP, a sensor of cardiac mechanical stretch, as an acetylated target of PCAF and HDAC4. We also show that trichostatin-A, a class I and II HDAC inhibitor, increases myofilament calcium sensitivity of wild-type, but not of MLP knock-out mice, thus demonstrating a role of MLP in acetylation-dependent increased contractile activity of myofilaments. These studies provide the first evidence that HATs and HDACs play a role in regulation of muscle contraction.