HDAC3-dependent reversible lysine acetylation of cardiac myosin heavy chain isoforms modulates their enzymatic and motor activity. [Cell Biology]
April 24th, 2015 by Samant, S. A., Pillai, V. B., Sundaresan, N. R., Shroff, S. G., Gupta, M. P.
Reversible lysine acetylation is a widespread post-translational modification controlling the activity of proteins in different sub-cellular compartments. We previously demonstrated that a class-II HDAC, HDAC4 and a HAT, PCAF associate with cardiac sarcomeres, and 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 immuno-histochemical and electron microscopic analyses we found that HDAC3 was localized to A-band of sarcomeres, and was 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 to 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, independent 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 first evidence for localization of HDAC3 at myofilaments and uncover a novel mechanism modulating the motor activity of cardiac MHC isoforms.