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 lig...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 motifcontaining 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-1βand IL-6 in endothelial cells.By contrast,overexpression of TRIM47 promoted inflammatory response and monocyte adhesion upon TNFαstimulation.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 TNFαsignaling 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.展开更多
基金supported by the National Natural Science Foundation of China(82070080 and 81860020 to Y.Q.,81873659 to H.-B.X.,and 81760140 and 81970256 to K.Y.D.)Foundation for the National Institutes of Health(1 R15AI138116 to M.F.)the financial support provided by China Scholarship Council(201906825031 to Y.Q.).
文摘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 motifcontaining 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-1βand IL-6 in endothelial cells.By contrast,overexpression of TRIM47 promoted inflammatory response and monocyte adhesion upon TNFαstimulation.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 TNFαsignaling 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.
