TRIM47 is a novel endothelial activation factor that aggravates lipopolysaccharide-induced acute lung injury in mice via K63-linked ubiquitination of TRAF2

被引:64
作者
Qian, Yisong [1 ,2 ]
Wang, Ziwei [1 ]
Lin, Hongru [1 ]
Lei, Tianhua [2 ]
Zhou, Zhou [2 ]
Huang, Weilu [1 ]
Wu, Xuehan [1 ]
Zuo, Li [1 ]
Wu, Jie [1 ]
Liu, Yu [1 ]
Wang, Ling-Fang [1 ]
Guan, Xiao-Hui [1 ]
Deng, Ke-Yu [1 ]
Fu, Mingui [2 ]
Xin, Hong-Bo [1 ]
机构
[1] Nanchang Univ, Natl Engn Res Ctr Bioengn Drugs & Technol, Inst Translat Med, 1299 Xuefu Rd, Nanchang 330031, Jiangxi, Peoples R China
[2] Univ Missouri, Sch Med, Dept Biomed Sci, 2411 Holmes St, Kansas City, MO 64108 USA
基金
中国国家自然科学基金; 美国国家卫生研究院;
关键词
SEVERE SEPSIS; DEGRADATION; PROTEIN; DYSFUNCTION; PROGRESSION; PROMOTES; IMMUNITY; CANCER; GENE;
D O I
10.1038/s41392-022-00953-9
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Endothelial activation plays an essential role in the pathogenesis of sepsis-induced acute lung injury, however, the detailed regulatory mechanisms remain largely unknown. Here, we reported that TRIM47, an E3 ubiquitin ligase of the tripartite motif-containing protein family, was highly expressed in vascular endothelial cells. TRIM47-deficient mice were effectively resistant to lipopolysaccharide (LPS)-induced acute lung injury and death by attenuating pulmonary inflammation. TRIM47 was upregulated during TNF alpha-induced endothelial activation in vitro. Knockdown of TRIM47 in endothelial cells inhibited the transcription of multiple pro-inflammatory cytokines, reduced monocyte adhesion and the expression of adhesion molecules, and suppressed the secretion of IL-1 beta and IL-6 in endothelial cells. By contrast, overexpression of TRIM47 promoted inflammatory response and monocyte adhesion upon TNF alpha stimulation. In addition, TRIM47 was able to activate the NF-kappa B and MAPK signaling pathways during endothelial activation. Furthermore, our experiments revealed that TRIM47 resulted in endothelial activation by promoting the K63-linked ubiquitination of TRAF2, a key component of the TNF alpha signaling pathway. Taken together, our studies demonstrated that TRIM47 as a novel activator of endothelial cells, promoted LPS-induced pulmonary inflammation and acute lung injury through potentiating the K63-linked ubiquitination of TRAF2, which in turn activates NF-kappa B and MAPK signaling pathways to trigger an inflammatory response in endothelial cells.
引用
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页数:12
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