ZDHHC9‐mediated palmitoylation promotes hypertrophic signaling in the heart

Abstract

Heart disease remains a leading cause of mortality in the United States, 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‐acyl transferases, 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. In HEK‐293 cells, the Golgi‐localized acyl transferase, zDHHC9, was shown to palmitoylate and induce plasma membrane localization and activation of H‐Ras and N‐Ras, members of the Ras family of membrane‐localized GTPases. Activation of Ras enhances the activity of downstream pathways such as the ERK/MAP kinase pathway and c‐Jun N‐terminal kinases (JNK), which induce pathological cardiac remodeling in the heart. To investigate the potential roles of zDHHC9 in cardiac pathogenesis, we generated a transgenic mouse model with cardiomyocyte‐specific overexpression of zDHHC9 (Tg‐Zdhhc9). These mice exhibited cardiac hypertrophy with increased ventricular wall thickness at 6 months of age. At 8 months of age, Tg‐Zdhhc9 mice showed impaired cardiac contractile function and severe dilated cardiomyopathy. Interestingly, there were no significant differences in palmitoylation of H‐Ras in Tg‐Zdhhc9 hearts compared to control hearts, indicating that zDHHC9‐triggered cardiac hypertrophy may be due to palmitoylation of other substrates in cardiomyocytes. Ongoing work is utilizing unbiased quantitative palmitoyl proteomics to identify novel zDHHC9 substrates that mediate activation of hypertrophic signaling in the cardiomyocytes. Altogether, these data suggest zDHHC9‐mediated palmitoylation contributes to hypertrophic signaling and heart disease.Support or Funding InformationThis work was supported by National Heart, Lung and Blood Institute grant R00‐HL‐36695 (MJB).