HDAC4 and PCAF bind to cardiac sarcomeres and play a role in regulating myofilament contractile activity.
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 sarcomeres. 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.
Gupta
Mahesh P
MP
Department of Surgery, Committee on Molecular Medicine, Biological Science Division, University of Chicago, 5841 S. Maryland Avenue, Chicago, IL 60637, USA. mgupta@surgery.bsd.uchicago.edu
Samant
Sadhana A
SA
Smith
Stephen H
SH
Shroff
Sanjeev G
SG
D008841:Actin Cytoskeleton / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure; D000818:Animals; D002118:Calcium / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006877:Hydroxamic Acids / Q000494:pharmacology; D060588:LIM Domain Proteins; D051379:Mice; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D009200:Myocardial Contraction / Q000502:physiology*; D009206:Myocardium / Q000201:enzymology* / Q000648:ultrastructure; D032383:Myocytes, Cardiac; D011817:Rabbits; D051381:Rats; D012518:Sarcomeres / Q000201:enzymology* / Q000235:genetics / Q000648:ultrastructure; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism; D050880:p300-CBP Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000099224:p300-CBP-Associated Factor
D002118:Calcium; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D006877:Hydroxamic Acids; D060588:LIM Domain Proteins; D009124:Muscle Proteins; D033921:Vesicular Transport Proteins; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C512942:Marcksl1 protein, rat; C090114:cysteine and glycine-rich protein 3; C012589:trichostatin A; C498618:Hdac5 protein, mouse