The E3 ubiquitin ligase SMURF2 protects against atherosclerosis by inhibiting endothelial inflammation

Abstract

Endothelial dysfunction is a key driver of sustained and chronic vascular inflammation, which plays a critical role in the progression of atherosclerotic disease. Despite its significance, the molecular mechanisms underlying vascular endothelial inflammation remain poorly understood. Ubiquitination, a widespread post-translational modification, regulates a wide range of biological processes and is essential for maintaining cellular homeostasis in both physiological and pathological conditions. Numerous studies have highlighted the intricate interplay between vascular endothelial inflammation and ubiquitination. In this study, we identified a novel function for the HECT-type E3 ubiquitin ligase SMURF2 in modulating endothelial inflammation and atherosclerosis. Endothelial-specific overexpression of SMURF2 in mice significantly attenuated vascular endothelial inflammation and slowed atherosclerosis progression, a result that was further corroborated through in vitro experiments. At the mechanistic level, we demonstrated that HMGB1 is a novel substrate of SMURF2, with this interaction being enhanced under inflammatory conditions. Moreover, the WW domain of SMURF2 interacts with the HMG-B box domain of HMGB1, promoting its K48-linked ubiquitination and subsequent proteasomal degradation. In conclusion, our findings emphasize the pivotal role of endothelial SMURF2 and the SMURF2-HMGB1 regulatory axis in controlling vascular endothelial inflammation and atherosclerosis, suggesting that SMURF2 represents a promising therapeutic target for atherosclerotic disease.