Defining the role of DHHC3 in cardiac stress signaling

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Project Summary Heart failure remains a significant contributor to both cardiovascular disease and death and it is predicted to continue to increase in prevalence. A further understanding of the molecular mechanisms contributing to heart failure will serve to catalyze development of novel therapeutics to treat this disease. Lipid modification of proteins plays important roles in both their function and localization. Numerous cardiac signaling molecules require lipidation modification, including small GTPases and heterotrimeric G-proteins. In fact, the molecular mechanism of statins in treating cardiac hypertrophy is partially attributed to preventing membrane localization of Rho GTPases by blocking prenylation. Rho GTPases are also S-palmitoylated but unlike prenylation, S-palmitoylation is a reversible lipid modification that controls dynamic GTPase association with the plasma membrane and their activity. S-palmitoylation is executed by the recently discovered family of palmitoyl acyltransferases (PATs), which contain a conserved zinc finger like aspartate-histidine-histidine-cystine (zDHHC) domain for which the family of proteins are named. The outlined proposal seeks to elucidate how DHHC proteins underlie cardiac signal transduction, and more specifically, how the Golgi localized DHHC3 (Godz) protein causes pathology. Preliminary data from the lab showed that cardiac overexpression of Godz in mice results in congestive heart failure preceded by enhanced palmitoylation, expression, and activity of RhoGTPase in heart. RhoGTPases have known roles in cardiac stress signaling underlying pathological hypertrophy. This led us to hypothesize that Godz represents a novel mediator of stress induced pathological signaling in the heart. Two specific aims are proposed to examine Godz in cardiac function. Aim 1: Examine mechanisms whereby Godz-mediated intracellular signaling promotes disease in hearts of transgenic mice. Aim 2: Determine the physiologic relevance of Godz function in pathological hypertrophy. Together, these studies will substantially increase our knowledge of palmitoylation dependent signaling pathways in heart which may represent a novel therapeutic target for treatment of heart disease.