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Palmitoylation‐Dependent Regulation of RhoGTPase Signaling and Cardiac Pathophysiology

S‐palmitoylation is a reversible lipid modification that regulates protein trafficking, localization, and function by providing a lipid tag that serves as a molecular instruction for association with specific cellular membranes. S‐palmitoylation is catalyzed by the zinc finger Asp‐His‐His‐Cys (zDHHC) family of S‐acyl transferases, however the role of these enzymes in the regulation of signal transduction in cardiomyocytes and its effects on cardiac pathophysiology are not well understood. To identify zDHHC enzymes with important regulatory functions in the heart, we used AAV9 to screen for the effects of overexpression of different zDHHC enzymes in the heart. Overexpression of the Golgi‐localized enzyme zDHHC3 resulted in severe cardiomyopathy, an effect that was not observed with overexpression of plasma membrane‐localized zDHHC5, endoplasmic reticulum‐localized zDHHC6, or Golgi‐localized zDHHC13. These data suggest important signaling mechanisms regulated by zDHHC3‐mediated palmitoylation at the cardiomyocyte Golgi apparatus. We next generated mice with cardiomyocyte‐specific overexpression of zDHHC3 to further investigate signaling mediated by this enzyme in the heart. Overexpression of zDHHC3 resulted in cardiomyopathy and congestive heart failure that was preceded by an unprecedented induction of all Rho family small GTPases, including RhoA, Rac1, Cdc42, and RhoGDI. Importantly, transgenic mice overexpressing an enzymatically‐dead mutant of zDHHC3 did not induce RhoGTPase signaling or develop cardiac disease. Quantitative palmitoyl proteomics in zDHHC3 overexpressing cells identified Rac1 as a novel substrate of zDHHC3. Rac1 palmitoylation, plasma membrane localization, activity, and downstream hypertrophic signaling were substantially increased in zDHHC3 overexpressing hearts, implicating zDHHC3‐mediated palmitoylation of Rac1 as an important signaling circuit in cardiomyocytes. Taken together, these data indicate that zDHHC3 functions as a novel effector of Rho family of small GTPases and suggest that inhibition of zDHHC3 acyl transferase activity may represent a novel therapeutic strategy to treat cardiac disease or other diseases associated with enhanced RhoGTPase signaling.