Toll/IL-1 receptor domain-containing adaptor inducing IFN-β (TRIF) associates with TNF receptor-associated factor 6 and TANK-Binding kinase 1, and activates two distinct transcription factors, NF-κB and IFN-regulatory factor-3, in the toll-like receptor signaling
Toll/IL-1 receptor domain-containing adaptor inducing IFN-β (TRIF) associates with TNF receptor-associated factor 6 and TANK-Binding kinase 1, and activates two distinct transcription factors, NF-κB and IFN-regulatory factor-3, in the toll-like receptor signaling
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DOI：
10.4049/jimmunol.171.8.4304
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发表时间：
2003-10-15
影响因子：
4.4
通讯作者：
Akira, S
中科院分区：
文献类型：
--
作者：
Sato, S;Sugiyama, M;Akira, S
我们以前报道了一个新的Toll/IL-1 R（TIR）的分子，命名为TIR域含有衔接诱导IFN-β（TRIF）。尽管初步研究表明TRIF不仅具有激活NF-κ B依赖性启动子的能力，而且具有激活IFN-β启动子的能力，但TRIF诱导的信号传导的分子机制知之甚少。在这项研究中，我们调查了通过TRIF的信号级联。TNF受体相关因子（TRAF）6通过TRAF 6的TRAIT结构域和TRIF N端部分的TRAF 6结合基序与TRIF相互作用。TRIF的TRAF 6结合基序的破坏使其不能与TRAF 6结合，并导致TRIF诱导的NF-κ B依赖性启动子而不是IFN-β启动子的激活减少。TANK-binding kinase（TBK）-1是最近报道的IFN调节因子-3的激酶，IFN调节因子-3是IFN-β表达所必需的转录因子，也与TRIF的N-末端区域相关。此外，TRIF和TBK 1之间的关联似乎需要TBK 1的激酶活性以及TRIF的磷酸化。由于TRAF 6和TBK 1结合在TRIF区域附近，因此TRAF 6似乎在物理上阻止了TRIF和TBK 1之间的结合。总之，这些结果表明TRIF与TRAF 6和TBK 1独立地结合，并分别激活两种不同的转录因子NF-κ B和IFN调节因子-3。
We previously reported a new Toll/IL-1R (TIR)-containing molecule, named TIR domain-containing adaptor inducing IFN-beta (TRIF). Although initial study indicated that TRIF possesses the ability,to activate not only the NF-kappaB-dependent but also the IFN-beta promoters, the molecular mechanisms of TRIF-induced signaling are poorly understood. In this study, we investigated the signaling cascades through TRIF. TNF receptor-associated factor (TRAF)6 interacted with TRIF through the TRAIT domain of TRAF6 and TRAF6-binding motifs found in the N-terminal portion of TRIF. Disruption of TRAF6-binding motifs of TRIF disabled it from associating with TRAF6, and resulted in a reduction in the TRIF-induced activation of the NF-kappaB-dependent but not IFN-beta promoter. TANK-binding kinase (TBK)-1, which was recently reported to be a kinase of IFN regulatory factor-3, which is an essential transcription factor for IFN-beta expression, also associated with the N-terminal region of TRIF. Moreover, the association between TRIF and TBK1 appeared to require the kinase activity of TBK1, as well as phosphorylation of TRIF. Because TRAF6 and TBK1 bind close the region of TRIF, it seems that TRAF6 physically prevents the association between TRIF and TBK1. Taken together, these results demonstrate that TRIF associates with TRAF6 and TBK1 independently, and activates two distinct transcription factors, NF-kappaB and IFN regulatory factor-3, respectively.