Ubiquitin like protein FAT10 repressed cardiac fibrosis after myocardial ischemic via mediating degradation of Smad3 dependent on FAT10-proteasome system

Cardiac fibrosis after myocardial ischemic (MI) injury is a key factor in heart function deterioration. We recently showed that ubiquitin-like protein human HLA-F adjacent transcript (FAT10) plays a novel role in ischemic cardiovascular diseases, but its function in cardiac fibrosis remains unknown. The present study aims to detail the pathophysiological function of FAT10 in MI injury-induced cardiac fibrosis and its underlying mechanism. In vivo, a systemic FAT10 deficiency mouse (Fat10(-/-)) model was established which exhibited excessive cardiac fibrosis and deleterious cardiac function after MI when compared to wild-type mice. Cardiac fibrotic-related proteins (alpha-SMA, collagen I and collagen III) content were increased in MI-Fat10(-/-) mice. Similarly, cardiac FAT10 restoration in Fat10(-/-) mice suppressed fibrosis and improved cardiac function. In vitro, FAT10 overexpression exert a protective effect against the transforming growth beta 1 (TGF-beta 1)-induced proliferation, migration and differentiation in cardiac fibroblast (CFs), primary CFs from Fat10(-/-) mice and human induced pluripotent stem cell-derived CFs (hiPSC-CFs). Furthermore, immunoprecipitation-mass spectrometry (IP-MS) data demonstrated that FAT10 might mediate Smad3, a critical factor in cardiac fibrosis. Combined with rescue assays both in vivo and vitro, the protective effects of FAT10 against cardiac fibrosis was detected to be dependent on Smad3. In depth, Smad3 as a FAT10 specific substrate, FAT10 specifically bind to the K378 site of Smad3 directly via its C-terminal glycine residues and mediated the degradation of Smad3 through the FAT10-proteasome system instead of ubiquitin. In conclusion, we here show that FAT10 is a novel regulator against cardiac fibrosis after MI by mediating Smad3 degradation through FAT10-mediated proteasome system. Our study confirms the cardioprotective role of FAT10 in the heart, and providing a new prospective insight into the regulation of cardiac fibrosis after MI.

Automated summary

This study investigates the role of FAT10 in cardiac fibrosis after myocardial ischemic injury and its underlying mechanism. The results show that FAT10 deficiency in mice leads to excessive cardiac fibrosis and deteriorated cardiac function after myocardial ischemic injury, while restoration of FAT10 suppresses fibrosis and improves cardiac function. In vitro experiments demonstrate that FAT10 overexpression protects cardiac fibroblasts against proliferation, migration, and differentiation induced by TGF-beta 1. The study also suggests that FAT10 may mediate the degradation of Smad3, a critical factor in cardiac fibrosis.