TRIM65 E3 ligase targets VCAM-1 degradation to limit LPS-induced lung inflammation
TRIM65 E3 ligase targets VCAM-1 degradation to limit LPS-induced lung inflammation作者机构：Department of Biomedical ScienceSchool of MedicineUniversity of Missouri-Kansas CityKansas CityMO 64108USA Institute of Translational MedicineNanchang UniversityNanchang 330031China Institute of Cardiovascular DiseasesDepartment of PathophysiologyHengyang Medical CollegeUniversity of South ChinaHengyang A21001China Department of Physiological SciencesCenter for Veterinary and Health sciencesOklahoma State UniversityStillwaterOK 7A078USA
出 版 物：《Journal of Molecular Cell Biology》 (分子细胞生物学报（英文版）)
年 卷 期：2020年第12卷第3期
页 面：190-201页
核心收录：
基 金：supported by American Heart Association Grant(17AIREA33660073) H.-B.X.by the National Natural Science Foundation of China(91639106)。
主 题：TRIM65 VCAM-1 endothelial activation lung inflammation ubiquitination
摘 要：Although the adhesion molecules-mediated leukocyte adherence and infiltration into tissues is an important step of inflammation,the post-translational regulation of these proteins on the endothelial cells is poorly understood.Here,we report that TRIM65,an ubiquitin E3 iigase of tripartite protein family,selectively targets vascular cell adhesion molecule 1(VCAM-1)and promotes its ubiq-uitination and degradation,by which it critically controls the duration and magnitude of sepsis-induced pulmonary inflammation.TRIM65 is constitutively expressed in human vascular endothelial cells.During TNFa-induced endothelial activation,the protein levels ofTRIM65 and VCAM-1 are inversely correlated.Expression of wild-type TRIM65,but not expression of aTRIM65 mutant that lacks E3 ubiquitin ligase function in endothelial cells,promotes VCAM-1 ubiquitination and degradation,whereas small interference RNA-mediated knockdown of TRIM65 attenuates VCAM-1 protein degradation.Further experiments show that TRIM65 directly interacts with VCAM-1 protein and directs its polyubiquitination,by which TRIM65 controls monocyte adherence and infiltration into tissues during inflammation.Importantly,TRIM65-deficient mice are more sensitive to lipopolysaccharide-induced death,due to sustained and severe pulmonary inflammation.Taken together,our studies suggest that TRIM65-mediated degradation of VCAM-1 represents a potential mechanism that controls the duration and magnitude of infiammation.
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