Kawai Taro, Sato Shintaro, Ishii Ken J, Coban Cevayir, Hemmi Hiroaki, Yamamoto Masahiro, Terai Kenta, Matsuda Michiyuki, Inoue Jun-ichiro, Uematsu Satoshi, Takeuchi Osamu, Akira Shizuo
ERATO, Akira Innate Immunity Program, Japan Science and Technology Agency, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan.
Nat Immunol. 2004 Oct;5(10):1061-8. doi: 10.1038/ni1118. Epub 2004 Sep 7.
Toll-like receptors (TLRs) are involved in the recognition of microbial pathogens. A subset of TLRs, TLR7, TLR8 and TLR9, induces antiviral responses by producing interferon-alpha (IFN-alpha). Production of IFN-alpha is dependent on the Toll-interleukin-1 receptor domain-containing adaptor MyD88. Here we show that MyD88 formed a complex with the transcription factor IRF7 but not with IRF3. The death domain of MyD88 interacted with an inhibitory domain of IRF7, and this interaction resulted in activation of the IFN-alpha-dependent promoters. Furthermore, the adaptor molecule TRAF6 also bound and activated IRF7. Ubiquitin ligase activity of TRAF6 was required for IRF7 activation. These results indicate that TLR-mediated IFN-alpha induction requires the formation of a complex consisting of MyD88, TRAF6 and IRF7 as well as TRAF6-dependent ubiquitination.
Toll样受体（TLRs）参与微生物病原体的识别。TLRs的一个亚组，即TLR7、TLR8和TLR9，通过产生α干扰素（IFN-α）诱导抗病毒反应。IFN-α的产生依赖于含Toll样白细胞介素-1受体结构域的接头分子髓样分化因子88（MyD88）。在此我们表明，MyD88与转录因子干扰素调节因子7（IRF7）形成复合物，但不与IRF3形成复合物。MyD88的死亡结构域与IRF7的一个抑制结构域相互作用，这种相互作用导致依赖IFN-α的启动子激活。此外，接头分子肿瘤坏死因子受体相关因子6（TRAF6）也结合并激活IRF7。TRAF6的泛素连接酶活性是IRF7激活所必需的。这些结果表明，TLR介导的IFN-α诱导需要由MyD88、TRAF6和IRF7组成的复合物的形成以及TRAF6依赖的泛素化。
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