Analysis of a TIR-less Splice Variant of TRIF Reveals an Unexpected Mechanism of TLR3-mediated Signaling
Analysis of a TIR-less Splice Variant of TRIF Reveals an Unexpected Mechanism of TLR3-mediated Signaling
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TRIF 无 TIR 剪接变体的分析揭示了 TLR3 介导的信号转导的意外机制
DOI：
10.1074/jbc.m109.072231
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发表时间：
2010-04-23
影响因子：
4.8
通讯作者：
Shu, Hong-Bing
中科院分区：
文献类型：
--
作者：
Han, Ke-Jun;Yang, Yan;Shu, Hong-Bing
Toll样受体3(TLR3)识别病毒RNA可激活转录因子NF-kappa B和IRF3，诱导I型干扰素的产生。TRIF是一种含Toll-IL-1受体(TIR)结构域的适配蛋白，在TLR3介导的信号转导中发挥重要作用。研究表明，TRIF与TLR3通过各自的TIR结构域相互作用。在本研究中，我们发现了TRIF的一个缺失TIR结构域的剪接变异体，命名为Tris。Tris的过表达激活了核因子-kappaB、干扰素刺激的反应元件(ISRE)和干扰素-β启动子，而Tris的敲除则抑制了TLR3介导的信号转导，提示Tris参与了TLR3介导的信号转导。此外，我们还鉴定了Tris或TRIF的N-末端与TBK1结合的基序，该基序对其与TBK1的相互作用和激活ISRE的能力是重要的。Tris激活ISRE还需要其C端RIP同型相互作用基序介导的二聚化或寡聚化。最后，我们证明了在Poly(I-C)激活TLR3的过程中，Tris与TRIF相关。这些发现揭示了TLR3介导的信号传递的一种意想不到的机制。
Recognition of viral RNA by Toll-like receptor 3 (TLR3) triggers activation of the transcription factors NF-kappa B and IRF3 and induction of type I interferons. TRIF is a Toll-interleukin 1 receptor (TIR) domain-containing adapter protein critically involved in TLR3-mediated signaling. It has been shown that TRIF interacts with TLR3 through their respective TIR domains. In this study, we identified a splice variant of TRIF lacking the TIR domain, which is designated as TRIS. Overexpression of TRIS activates NF-kappa B, interferon-stimulated response element (ISRE), and the interferon-beta promoter, whereas knockdown of TRIS inhibited TLR3-mediated signaling, suggesting that TRIS is involved in TLR3-mediated signaling. Furthermore, we identified an N-terminal TBK1-binding motif of TRIS or TRIF that was important for its interaction with TBK1 and ability to activate ISRE. Activation of ISRE by TRIS also needs its dimerization or oligomerization mediated by its C-terminal RIP homotypic interaction motif. Finally, we demonstrated that TRIS was associated with TRIF upon TLR3 activation by poly(I-C). These findings reveal an unexpected mechanism of TLR3-mediated signaling.