Syntenin negatively regulates TRAF6-mediated IL-1R/TLR4 signaling
Syntenin negatively regulates TRAF6-mediated IL-1R/TLR4 signaling
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Syntenin 负向调节 TRAF6 介导的 IL-1R/TLR4 信号传导。
DOI：
10.1016/j.cellsig.2007.12.002
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发表时间：
2008-04-01
影响因子：
4.8
通讯作者：
Chen, Danying
中科院分区：
文献类型：
--
作者：
Chen, Fang;Du, Yijuan;Chen, Danying
Toll样受体参与宿主对入侵病原体的防御。这个超家族的两个成员，IL-1R和TLR4，激活重叠的NF-kappa B激活TRAF6介导的信号通路。在这项研究中，我们发现Syntenin是IL-1R和TLR4介导的NF-kappa B激活的负调控因子。过表达的Syntenin以剂量依赖方式抑制IL-1或LPS诱导的NF-kappaB活化和IL-8mRNA表达，但不能抑制TNF诱导的NF-kappa B激活和IL-8mRNA表达。在人293细胞中，Syntenin与TRAF6特异地相互作用，并抑制TRAF6诱导的核因子-kappaB和AP-1的激活。Syntenin在生理条件下也与TRAF6结合，在IL-1刺激下与TRAF6解离。这可能是由于Syntenin和IRAK1之间的竞争，因为IRAK1的过表达破坏了Syntenin与TRAF6的相互作用，并挽救了Syntenin导致TRAF6泛素化的减少。此外，敲除Syntenin可增强IL-1或内毒素诱导的NF-kappa B活化和IL-8mRNA表达。这些发现表明，Syntenin是TRAF6的生理抑制因子，并在IL-1R和TLR4介导的NF-kappa B激活途径中发挥抑制作用。(C)2007 Elsevier Inc.保留所有权利。
Toll-like receptors are involved in host defense against invading pathogens. The two members of this superfamily, IL-1R and TLR4, activate overlapping NF-kappa B activate signaling pathway mediated by TRAF6. In this study, we identified Syntenin as a negative regulator of IL-1R and TLR4 mediated NF-kappa B activation. Overexpressed Syntenin inhibited IL-1- or LPS-, but not TNF- induced NF-kappa B 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-kappa B 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-kappa B 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-kappa B activation pathways. (C) 2007 Elsevier Inc. All rights reserved.