TRAM is specifically involved in the Toll-like receptor 4-mediated MyD88-independent signaling pathway
TRAM is specifically involved in the Toll-like receptor 4-mediated MyD88-independent signaling pathway
复制标题
DOI：
10.1038/ni986
复制
发表时间：
2003-11-01
影响因子：
30.5
通讯作者：
Akira, S
中科院分区：
文献类型：
--
作者：
Yamamoto, M;Sato, S;Akira, S
Toll样受体(TLRs)对病原体的识别通过Toll-IL-1受体(TIR)结构域适配器MyD88、TIRAP和TRIF等介导的信号通路来触发先天免疫反应。MyD88是一种常见的接头，对致炎细胞因子的产生是必不可少的，而TRIF从TLR3和TLR4介导MyD88不依赖于MyD88的途径。在这里，我们鉴定了第四个含有TIR结构域的接头，TRIF相关接头分子(TRAM)，并通过基因打靶分析了它的生理功能。TRAM缺陷小鼠对TLR4配体的反应表现出细胞因子产生的缺陷，但对其他TLR配体没有反应。在TRAM缺陷的细胞中，TLR4而不是TLR3介导的MyD88非依赖干扰素的产生和信号级联的激活被取消。因此，TRAM为TLR4信号的MyD88非依赖性成分提供了特异性。
Recognition of pathogens by Toll-like receptors (TLRs) triggers innate immune responses through signaling pathways mediated by Toll-interleukin 1 receptor (TIR) domain-containing adaptors such as MyD88, TIRAP and TRIF. MyD88 is a common adaptor that is essential for proinflammatory cytokine production, whereas TRIF mediates the MyD88-independent pathway from TLR3 and TLR4. Here we have identified a fourth TIR domain-containing adaptor, TRIF-related adaptor molecule (TRAM), and analyzed its physiological function by gene targeting. TRAM-deficient mice showed defects in cytokine production in response to the TLR4 ligand, but not to other TLR ligands. TLR4- but not TLR3-mediated MyD88-independent interferon-production and activation of signaling cascades were abolished in TRAM-deficient cells. Thus, TRAM provides specificity for the MyD88-independent component of TLR4 signaling.