ZDHHC14-Mediated Palmitoylation of TBK1 Promotes Pathological Cardiac Hypertrophy via Type I Interferon Signaling Activation

Abstract

Pathological cardiac hypertrophy represents a common maladaptive response to cardiovascular stress and constitutes a major harbinger of heart failure. Although S-palmitoylation--a reversible post-translational modification--critically governs protein localization, trafficking, and stability, its involvement in cardiac hypertrophy remains poorly characterized. In this study, we aimed to explore the role and regulatory mechanism of a palmitoyltransferase, zinc finger DHHC-type palmitoyltransferase 14 (ZDHHC14), in cardiac hypertrophy. We found that ZDHHC14 was significantly upregulated in cardiac hypertrophy tissues from both human patients and mouse models. Cardiomyocyte-specific ZDHHC14 knockdown ameliorated transverse aortic constriction (TAC)-induced cardiac hypertrophy and dysfunction in male mice, whereas cardiac-specific ZDHHC14 overexpression via AAV9 exacerbated these pathological phenotypes. Mechanistically, TANK-binding kinase 1 (TBK1) was identified as a novel substrate of ZDHHC14 through interactomic screening. ZDHHC14 catalyzed TBK1 palmitoylation at cysteine 267, which in turn facilitated TBK1 phosphorylation and subsequent activation of type I interferon (IFN-I) signaling, ultimately promoting cardiac hypertrophy. Importantly, our findings demonstrate that the TBK1-C267S mutation rectifies ZDHHC14 overexpression-induced exacerbation of cardiac hypertrophy. This study illustrated a ZDHHC14-TBK1-IFN-I axis in regulating cardiac hypertrophy, which may provide a potential therapeutic target to ameliorate pathological cardiac hypertrophy.