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

Yisong Qian, Ziwei Wang, Hongru Lin, Tianhua Lei, Zhou Zhou, Weilu Huang, Xuehan Wu, Li Zuo, Jie Wu, Yu Liu, Ling-Fang Wang, Xiao-Hui Guan, Ke-Yu Deng, Mingui Fu, Hong-Bo Xin

Signal transduction and targeted therapy 2022 May 06

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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 TNFα-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-1β and IL-6 in endothelial cells. By contrast, overexpression of TRIM47 promoted inflammatory response and monocyte adhesion upon TNFα stimulation. In addition, TRIM47 was able to activate the NF-κB 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 TNFα 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-κB and MAPK signaling pathways to trigger an inflammatory response in endothelial cells. © 2022. The Author(s).

Citation

Yisong Qian, Ziwei Wang, Hongru Lin, Tianhua Lei, Zhou Zhou, Weilu Huang, Xuehan Wu, Li Zuo, Jie Wu, Yu Liu, Ling-Fang Wang, Xiao-Hui Guan, Ke-Yu Deng, Mingui Fu, Hong-Bo Xin. TRIM47 is a novel endothelial activation factor that aggravates lipopolysaccharide-induced acute lung injury in mice via K63-linked ubiquitination of TRAF2. Signal transduction and targeted therapy. 2022 May 06;7(1):148