A novel and important role of UFM1‐binding protein 1 (UFBP1) in the regulation of ER and cardiac homeostasis

Abstract

Protein modifications by ubiquitin and ubiquitin‐like proteins are emerging as an important mechanism regulating heart function. 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 remains unclear. 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 during ageing and increased the propensity to heart failure in response to hemodynamic stress. 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, UFL1 controls the expression of UFBP1. Depletion of both UFL1 and UFBP1 in cultured cardiomyocytes aggravated ER stress‐induced cell injury. 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.