Spatiotemporal mobilization of Toll/IL-1 receptor domain-containing adaptor molecule-1 in response to dsRNA
Spatiotemporal mobilization of Toll/IL-1 receptor domain-containing adaptor molecule-1 in response to dsRNA
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DOI：
10.4049/jimmunol.179.10.6867
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发表时间：
2007-11-15
影响因子：
4.4
通讯作者：
Matsumoto, Misako
中科院分区：
文献类型：
--
作者：
Funami, Kenji;Sasai, Miwa;Matsumoto, Misako
TLR 3识别病毒dsRNA并诱导抗病毒免疫应答。TLR 3介导的细胞活化依赖于含有Toll/IL-1 R（TIR）结构域的衔接子分子-1（TICAM-1，也称为含有TIR结构域的衔接子诱导IFN-β或TRIF），其募集下游信号传导分子以活化转录因子IFN调节因子3（IRF-3）和NF-κ B。TICAM-1被激活和传输信号的机制在很大程度上仍然未知。在这项研究中，我们表明，TICAM-1改变其分布概况从一个弥漫的细胞质形式的斑点状结构，以响应dsRNA。受体相互作用蛋白1（RIP 1）是TICAM-1介导的NF-κ B活化的关键信号分子，在TICAM-1斑点中积累。此外，NF-κ B活化激酶相关蛋白1（NAP 1），一种连接TICAM-1和IRF-3活化激酶TBK 1（TANK结合激酶1）的下游分子，也被募集到TICAM-1斑点中。值得注意的是，在广泛形成TICAM-1斑点之前观察到TICAM-1和TLR 3的短暂共定位。因此，TICAM-1响应dsRNA的时空移动和含有RIP 1和NAP 1的TICAM-1斑点的形成对于TLR 3-TICAM-1途径的激活是重要的。
TLR3 recognizes viral dsRNA and induces antiviral immune responses. TLR3-mediated cell activation relies on Toll/IL-1R (TIR) domain-containing adaptor molecule-1 (TICAM-1, also named TIR domain-containing adaptor inducing IFN-beta or TRIF), which recruits downstream signaling molecules to activate the transcription factors IFN regulatory factor 3 (IRF-3) and NF-kappa B. The mechanisms by which TICAM-1 is activated and transmits signals remain largely unknown. In this study we show that TICAM-1 alters its distribution profile from a diffuse cytoplasmic form to a speckle-like structure in response to dsRNA. The receptor-interacting protein 1 (RIP1), a crucial signaling molecule for TICAM-1-mediated NF-kappa B activation, accumulated in the TICAM-1 speckles. In addition, NF-kappa B-activating kinase-associated protein 1 (NAP1), a downstream molecule linking TICAM-1 and the IRF-3-activating kinase TBK1 (TANK-binding kinase 1), was also recruited to the TICAM-1 speckles. Notably, a transient colocalization of TICAM-1 and TLR3 was observed before the extensive formation of the TICAM-1 speckles. Thus, the spatiotemporal mobilization of TICAM-1 in response to dsRNA and the formation of the TICAM-1 speckles containing RIP1 and NAP1 are important for the activation of the TLR3-TICAM-1 pathway.