Abstract 19192: Deciphering the Cardioprotective Role of Ufm1 Modification in Cardiac Remodeling

Abstract

UFM1 (ubiquitin-fold modifier 1) is a novel Ub-like protein that covalently modifies protein substrates via a highly conserved E1 (UBA5)-E2 (UFC1)-E3 (UFL1) enzymatic cascade. UFM1 modification (ufmylation) controls multiple pathophysiological events and is implicated in various human diseases. However, the significance of ufmylation in cardiac health remains poorly understood. We have previously reported that ufmylation is upregulated in compensated, hypertrophic mouse hearts but decreased in failing human hearts. Inhibition of ufmylation by targeted ablation of the E3 UFM1 ligase 1 (UFL1) in mouse hearts resulted in dilated cardiomyopathy under baseline and stress conditions. Targeted deletion of a putative UFM1 target, UFBP1, also evokes endoplasmic reticulum (ER) stress, leading to dilated cardiomyopathy While these exciting data reveal the pivotal role of ufmylation in the maintenance of ER/cardiac homeostasis, it remains unclear whether ufmylation of cardiac proteins is required for heart function and if so, how ufmylation regulates cardiac function. To determine the role of UFM1 modification in cardiomyocytes we have generated cardiac specific UFM1 CKO mice. The UFM1 CKO mice developed dilated cardiomyopathy at resting condition, as indicated by left ventricle (LV) wall thinning, chamber dilatation and impaired contractility at 4 months of age, which were further exacerbated by 6 months. To test the hypothesis that UFM1 protects the heart by modifying cardiac proteins we replenished UFM1-deficient mice with WT and conjugation deficient UFM1 via AAV9. Restoration of WT-UFM1 expression, but not the conjugation-deficient mutant, attenuated cardiac dysfunction of UFM1CKO hearts. It appears that UFM1 modification constraints pathological cardiac remodeling by maintaining ER homeostasis. Taken together, our data show that Ufmylation is a critical post-translational modification that regulates cardiac homeostasis.