Abstract P286: Acetylation Affords Enhanced Proteolytic Function in Normal and Diseased Myocardium

Proteasome complexes have essential implications on protein homeostasis and myocardial viability under stress. In the heart, the dynamics of proteasome complexes is regulated by post-translational modifications. In particular, acetylation contributes to the adjustment of cardiac functional proteome. However, the regulation of proteasome complexes by acetylation remains largely unknown. We characterized the acetylome (N-terminal and lysine acetylation) of cardiac 20S proteasomes using proteomic technology. With targeted enrichment, eight sites of lysine acetylation and nine sites of N-terminal acetylation were captured, which constituted the first comprehensive acetylome map of cardiac 20S proteasomes. Among them, six sites of lysine acetylation were inducible with pharmacological inhibitors of histone de-acetylases (HDACs). Both in vitro and in vivo assays demonstrated that HDACs inhibition led to elevated proteasome function. With purified 20S proteasomes, this impact directly related to acetylation modifications. Significantly, this endogenous regulatory mechanism manifests in both clinical and murine model of diseased myocardia. Proteasome biology is modulated by acetylation modifications in the heart. The potency of this regulatory mechanism was demonstrated in both mouse and human species. Moreover, this inherent rheostat effects in both acutely pathological murine model of ischemia-reperfusion and chronically pathological model of end-stage heart failure. With the novel observation made in this investigation, restoration of proteasomal function via pharmacological application after stress turns feasible.