S‐acyltransferase zDHHC9 Promotes Pathogenic Signaling in the Heart

Abstract

Heart disease remains a leading cause of mortality, contributing to over 600,000 deaths per year in the United States. Notwithstanding, the molecular mechanisms underlying the pathophysiology of heart disease remain largely elusive. Receptors, ion channels, and signaling proteins that regulate cardiac contractility and physiology are modified by post-translational modifications such as phosphorylation. Recent research into the roles of S-acylation or palmitoylation, the reversible post-translational modification of proteins with fatty acids, has demonstrated critical functions in the regulation of intracellular signaling in physiology and disease. Palmitoylation, which is catalyzed by the zinc finger Asp-His-His-Cys (zDHHC) family of S-acyltransferases, has been implicated in trafficking, stability, sorting and binding of proteins to cofactors. However, the roles of palmitoylation in cardiac signal transduction and cardiac pathogenesis are not well understood. Our preliminary work indicates that cardiac-specific transgenic overexpression of the Golgi-specific acyl transferase zDHHC9 (TgZdhhc9) results in cardiac hypertrophy and severe cardiomyopathy at six and eight months of age respectively in mice. Furthermore, using unbiased palmitoyl proteomics, we discovered that zDHHC9 palmitoylates Rab3 GTPase-activating protein catalytic subunit (Rab3gap1) that hydrolyzes the active GTP-bound form of Rab3 GTPase protein (Rab3) and inactivates Rab3 function. More so, mice subjected to transverse aortic constriction surgery, a pressure-overload model of pathological cardiac hypertrophy, showed increased palmitoylation of Rab3gap1, compared to sham controls. In addition, we observed that overexpression of zDHHC9 resulted in retention of Rab3gap1 at the Golgi and post-Golgi vesicles in cardiomyocytes and TgZdhhc9 hearts showed increased levels of Rab3a-GTP prior to disease onset, suggesting enhancement of cardiac Rab3a activity. Ongoing research will identify which hypertrophic signaling effectors are modulated by the zDHHC9/ Rab3gap1/Rab3a cascade in the heart. Altogether, these data suggest zDHHC9-mediated palmitoylation of Rab3gap1 may contribute to hypertrophic signaling and heart disease.