The adaptor molecule TIRAP provides signalling specificity for Toll-like receptors
The adaptor molecule TIRAP provides signalling specificity for Toll-like receptors
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DOI：
10.1038/nature01180
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发表时间：
2002-11-21
期刊：
影响因子：
64.8
通讯作者：
Medzhitov, R
中科院分区：
文献类型：
--
作者：
Horng, T;Barton, GM;Medzhitov, R
哺乳动物Toll样受体（TLR）作为感染传感器发挥作用，并诱导先天性和适应性免疫应答的激活（1-3）。在识别保守的病原体相关分子产物后，TLR通过其细胞内信号传导结构域、Toll/白细胞介素-1受体（TIR）结构域和下游衔接蛋白MyD 88激活宿主防御反应（参考文献1-3）。尽管TLR和白细胞介素-1（IL-1）受体家族的成员都通过MyD 88发出信号，但由各个受体诱导的信号传导途径不同。TIRAP是TLR信号传导途径中的衔接蛋白，已被鉴定并显示在TLR 4下游起作用（参考文献4、5）。在这里，我们报告的TIRAP基因缺陷的小鼠的一代。TIRAP缺陷小鼠对TLR 5、TLR 7和TLR 9配体以及IL-1和IL-18的反应正常，但在细胞因子产生和核因子NF-κ B和丝裂原活化蛋白激酶对脂多糖（TLR 4的配体）的反应中存在缺陷。此外，TIRAP缺陷型小鼠对TLR 2、TLR 1和TLR 6配体的应答也受损。因此，TIRAP差异性地参与TLR家族成员的信号传导，并且可以解释个体TLR的下游信号传导的特异性。
Mammalian Toll-like receptors (TLRs) function as sensors of infection and induce the activation of innate and adaptive immune responses(1-3). Upon recognizing conserved pathogen-associated molecular products, TLRs activate host defence responses through their intracellular signalling domain, the Toll/interleukin-1 receptor (TIR) domain, and the downstream adaptor protein MyD88 (refs 1-3). Although members of the TLR and the interleukin-1 (IL-1) receptor families all signal through MyD88, the signalling pathways induced by individual receptors differ. TIRAP, an adaptor protein in the TLR signalling pathway, has been identified and shown to function downstream of TLR4 ( refs 4, 5). Here we report the generation of mice deficient in the Tirap gene. TIRAP-deficient mice respond normally to the TLR5, TLR7 and TLR9 ligands, as well as to IL-1 and IL-18, but have defects in cytokine production and in activation of the nuclear factor NF-kappaB and mitogen-activated protein kinases in response to lipopolysaccharide, a ligand for TLR4. In addition, TIRAP-deficient mice are also impaired in their responses to ligands for TLR2, TLR1 and TLR6. Thus, TIRAP is differentially involved in signalling by members of the TLR family and may account for specificity in the downstream signalling of individual TLRs.