Syntenin negatively regulates TRAF6-mediated IL-1R/TLR4 signaling

Fang Chen, Yijuan Du, Zheng Zhang, Gang Chen, Min Zhang, Hong Bing Shu, Zhonghe Zhai, Danying Chen

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)666-674
Number of pages9
JournalCellular Signalling
Volume20
Issue number4
DOIs
StatePublished - Apr 2008

Bibliographical note

Funding Information:
This work was supported by National Natural Science Foundation of China (NSFC) (30421004 and 30570959), Foundation for the Author of National Excellent Doctoral Dissertation of PR China (FANEDD) (200533) and Chinese 973 Program (2006CB504301 and 2005CB724802). We thank Dr. Zhengfan Jiang for stimulating discussion and members of our laboratory for technical help.

Keywords

  • IL-1R
  • NF-κB
  • Syntenin
  • TLR4
  • TRAF6

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