Abstract 13465: UFM1 Binding Protein 1 (UFBP1) is Indispensable for Normal Heart Function and Endoplasmic Reticulum (ER) Homeostasis

Abstract

UFM1 (ubiquitin-fold modifier 1) is a novel ubiquitin-like protein that modifies protein targets via UFM1-specific conjugation enzymes. Dysregulation of UFM1 modification, termed ufmylation, has been linked to multiple human diseases but its importance in the heart remain unclear. We have previously reported that ufmylation is dysregulated in failing human hearts. Through deletion of the E3 UFM1 ligase 1 (UFL1) in mouse hearts, we demonstrated that ufmylation is essential for normal cardiac function and protects against pathological cardiac remodeling. However, how ufmylation exerts its cardioprotective effect remains unclear. Here, we report that UFBP1 (UFM1 binding protein 1), an ER-resident ufmylation target, is an important downstream effector of ufmylation in the heart. While deletion of UFBP1 in mouse hearts has no impact on ufmylation, the knockout (KO) mice developed dilated cardiomyopathy at resting condition, as indicated by left ventricular wall thinning, chamber dilatation and significantly decreased cardiac contractility at 6 months of age. Moreover, loss of UFBP1 exacerbated pressure overload-induced cardiac remodeling and dysfunction, recapitulating multiple aspects of the phenotypes of UFL1-deficient hearts. Mechanistically, inhibition of ufmylation destabilized UFBP1, and depletion of UFBP1 promoted ER stress-induced cell injury in cultured cardiomyocytes. Furthermore, excess ER stress is implicated in UFBP1KO hearts and is aggravated with the progression of cardiomyopathy. Interestingly, ER stress inducers upregulated the expression of ufmylation pathway components at both transcript and protein levels in cultured cardiomyocytes and mouse hearts, indicating an intimate cross-talk between ufmylation and ER stress. Collectively, our data identify a novel UFM1-UFL1-UFBP1 axis in constraining pathological cardiac remodeling and maintaining ER homeostasis.