Syntenin negatively regulates TRAF6-mediated IL-1R/TLR4 signaling.
Toll-like receptors are involved in host defense against invading pathogens. The two members of this superfamily, IL-1R and TLR4, activate overlapping NF-kappaB activate signaling pathway mediated by TRAF6. In this study, we identified syntenin as a negative regulator of IL-1R and TLR4 mediated NF-kappaB activation. Overexpressed syntenin inhibited IL-1- or LPS-, but not TNF- induced NF-kappaB activation and IL-8 mRNA expression in a dose dependent manner. Syntenin specifically interacted with TRAF6 in human 293 cells, and inhibited TRAF6 induced NF-kappaB and AP-1 activation. Syntenin also associated with TRAF6 under physiological condition, and dissociated from TRAF6 upon IL-1 stimulation. This might be due to a competition between syntenin and IRAK1, as overexpression of IRAK1 disrupted the interaction of syntenin with TRAF6, and rescued syntenin induced reduction of TRAF6 ubiquitination. Moreover, knockdown of syntenin potentiated IL-1- or LPS- triggered NF-kappaB activation and IL-8 mRNA expression. These findings suggest that syntenin is a physiological suppressor of TRAF6 and plays an inhibitory role in IL-1R- and TLR4- mediated NF-kappaB activation pathways.
Chen
Fang
F
College of Life Sciences, Peking University, Beijing 100871, China.
Du
Yijuan
Y
Zhang
Zheng
Z
Chen
Gang
G
Zhang
Min
M
Shu
Hong-Bing
HB
Zhai
Zhonghe
Z
Chen
Danying
D
D002460:Cell Line; D025461:Feedback, Physiological; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism; D011485:Protein Binding; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D053676:Syntenins / Q000235:genetics / Q000378:metabolism*; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014162:Transfection; D025801:Ubiquitin / Q000378:metabolism
D007375:Interleukin-1; D016209:Interleukin-8; D008070:Lipopolysaccharides; D016328:NF-kappa B; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D017472:Receptors, Interleukin-1; D053676:Syntenins; C495345:TLR4 protein, human; D048029:TNF Receptor-Associated Factor 6; D051197:Toll-Like Receptor 4; D018808:Transcription Factor AP-1; D025801:Ubiquitin; D053592:Interleukin-1 Receptor-Associated Kinases