Abstract P2003: ER-resident UFBP1 Maintains ER Homeostasis And Represses Cardiac Inflammation To Constrain Pathological Cardiac Remodeling

Abstract

Ufmylation is a novel protein modification by which protein substrates are covalently modified by the ubiquitin-like protein, UFM1 (ubiquitin-fold modifier 1) via a UFM1-specific E1-E2-E3 enzymatic cascade. Through its ability to regulate protein function, ufmylation participates in diverse pathophysiological events and is implicated in various human diseases. We recently reported that ufmylation is dysregulated by cardiomyopathy in both human and mouse hearts. Inhibition of ufmylation by targeting the E3 ligase, UFL1, in the heart evokes ER stress, leading to dilated cardiomyopathy and heart failure under resting and stress conditions, demonstrating its critical role in maintaining ER and cardiac homeostasis. However, how ufmylation regulates ER and cardiac function remain unclear. Here, we report that UFBP1 (UFM1 binding protein 1), an ER-resident ufmylation target, is a crucial downstream effector of ufmylation in the heart. UFBP1 is downregulated in UFL1-deficient hearts but upregulated in pressure overload hearts. Condition knockout (KO) of UFBP1 in mouse heart caused dilated cardiomyopathy during aging and exacerbated pressure overload-induced pathological cardiac remodeling. Of note, the timeline of disease progression in UFBP1 KO mice closely aligned with that of UFL1 KO mice. Transcriptomics analysis revealed the involvement of ER stress signaling and unexpectedly, inflammation in the pathogenesis. Biochemical analyses confirmed the pronounced ER stress, increased cytokine expression, and remarkable infiltration of inflammatory cells into the myocardium, which preceded the severe cardiac phenotype. Alleviation of ER stress via TUDCA administration mitigated UFBP1KO-induced cardiac dysfunction, suggesting a causal role of ER stress in the pathogenesis. Re-expression of wild-type UFBP1, but not its ER-binding–deficient mutant, in UFBP1 KO hearts rescued the pathological cardiac phenotype. UFPB1 expression was stabilized by UFL1, and depletion of UFBP1 in cardiomyocytes (CMs) induced ER stress and promoted cell death, recapitulating most aspects of UFL1-deficient CMs. Collectively, our data suggest that ER-resident UFBP1 represses ER stress and cardiac inflammation to constrain pathological cardiac remodeling.