Cardiac Lysine Acetylation

Acetylation of lysine residues on histones was first recognized as a post-translational modification nearly 50 years ago. In the years since, families of histone acetyltransferases and deacetylases have been discovered, and nuclear protein acetylation has emerged as paramount in chromatin remodeling and transcriptional regulation. In the heart, histone acetylation is a mediator of the transcriptional programs that underlie cardiomyocyte proliferation, differentiation, and cardiac remodeling in pathological hypertrophy.

Over the last decade, preoteomic studies have indicated that lysine acetylation extends beyond the nucleus. It has become apparent that lysine acetylation is a widespread, evolutionarily conserved post-translational modification whose scope rivals phosphorylation. Studies have shown that caloric restriction in mice is cardioprotective and leads to diminished acetylation of mitochondrial proteins, which in turn, correlates with reduced ROS production from the electron transport chain.

Given the emerging prominence of extra-nuclear lysine acetylation, we undertook a proteomic approach to characterize the broader lysine acetylome of guinea pig hearts. We found that in addition to nuclear and mitochondrial proteins, proteins of the excitation-contraction coupling axis are, likewise acetylated. Including Ca2+-handling proteins, RyR2 and SERCA2, and myofilament proteins such as myosin actin and troponin complex. In collaboration with Dr. Anthony Cammarato (Johns Hopkins) and Brandon Biesiadecki (Ohio State) we are probing thin filament acetylation dynamics in heart failure and its impact on myofilament function.

Selected Publications

Foster DB, Liu T, Rucker J, O’Meally RN, Devine LR, Cole RN, and O’Rourke B. The cardiac acetyl-lysine proteome. PLoS ONE. 2013. 8(7): p. e67513

Lin YH, Schmidt W, Fritz KS, Jeong MY, Cammarato A, Foster DB, Biesiadecki BJ, McKinsey TA, and Woulfe KC. Site-specific acetyl-mimetic modification of cardiac troponin i modulates myofilament relaxation and calcium sensitivity. J Mol Cell Cardiol. 2020. 139: p. 135-147.

Schmidt W, Madan A, Foster DB, and Cammarato A. Lysine acetylation of F-actin decreases tropomyosin-based inhibition of actomyosin activity. J Biol Chem. 2020. 295(46): p. 15527-15539