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-κB activate signaling pathway mediated by TRAF6. In this study, we identified Syntenin as a negative regulator of IL-1R and TLR4 mediated NF-κB activation. Overexpressed Syntenin inhibited IL-1- or LPS-, but not TNF- induced NF-κB 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-κB 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-κB 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-κB activation pathways.