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.
Mesh Terms:
Cell Line, Feedback, Physiological, Humans, Interleukin-1, Interleukin-1 Receptor-Associated Kinases, Interleukin-8, Lipopolysaccharides, NF-kappa B, Protein Binding, RNA Interference, RNA, Messenger, RNA, Small Interfering, Receptors, Interleukin-1, Signal Transduction, Syntenins, TNF Receptor-Associated Factor 6, Toll-Like Receptor 4, Transcription Factor AP-1, Transfection, Ubiquitin
Cell. Signal.
Date: Apr. 01, 2008
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