TNF receptor-associated factor-1 (TRAF1) negatively regulates Toll/IL-1 receptor domain-containing adaptor inducing IFN-β (TRIF)-mediated signaling
TNF receptor-associated factor-1 (TRAF1) negatively regulates Toll/IL-1 receptor domain-containing adaptor inducing IFN-β (TRIF)-mediated signaling
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DOI：
10.1002/eji.200535415
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发表时间：
2006-01-01
影响因子：
5.4
通讯作者：
Shu, HB
中科院分区：
文献类型：
--
作者：
Su, XQ;Li, S;Shu, HB
Toll 样受体 3 (TLR3) 通过识别病毒感染过程中产生的病毒双链 RNA 并介导 I 型 IFN 的诱导，在抗病毒反应中发挥重要作用。 TRIF 是一种含有 Toll/IL-1 受体 (TIR) 结构域的衔接蛋白，与 TLR3 相关，并关键参与 TLR3 介导的信号传导。在酵母双杂交筛选中，我们将 TNF 受体相关因子 (TRAF) 1 鉴定为 TRIF 相互作用蛋白。 TRAF1 的 TRAF-C 结构域和 TRIF 的 TIR 结构域负责它们的相互作用。 TRAF1 的过表达抑制 TRIF 和 TLR3 介导的 NF-κ B、IFN 刺激反应元件和 IFN-β 启动子的激活。 TRIF 的过度表达导致 TRAF1 的半胱天冬酶依赖性裂解。 TRAF1 的 N 端而非 C 端片段被切割，负责抑制 TRIF 信号传导。 TRAF1 的 caspase 裂解位点突变或添加 caspase 抑制剂 crmA 会抑制 TRAF1 裂解，并消除 TRAF1 抑制 TRIF 信号传导的能力，表明 TRIF 诱导的 TRAF1 裂解是其抑制 TRIF 信号传导所必需的。我们的研究结果为 TRIF 介导的信号传导的负调控提供了一种新机制。
Toll-like receptor 3 (TLR3) plays an important role in antiviral responses through recognizing viral double-stranded RNA produced during viral infection and mediating induction of type I IFN. TRIF is a Toll/IL-1 receptor (TIR) domain-containing adaptor protein that is associated with TLR3 and critically involved in TLR3-mediated signaling. In yeast two-hybrid screens, we identified TNF receptor-associated factor (TRAF) 1 as a TRIF-interacting protein. The TRAF-C domain of TRAF1 and the TIR domain of TRIF were responsible for their interaction. Overexpression of TRAF1 inhibited TRIF- and TLR3-mediated activation of NF-kappa B, IFN-stimulated response element and the IFN-beta promoter. Overexpression of TRIF caused caspase-dependent cleavage of TRAF1. The cleaved N-terminal but not C-terminal fragment of TRAF1 was responsible for inhibiting TRIF signaling. Mutation of the caspase cleavage site of TRAF1 or addition of the caspase inhibitor crmA inhibited TRAF1 cleavage and abolished the ability of TRAF1 to inhibit TRIF signaling, suggesting that TRIF-induced cleavage of TRAF1 is required for its inhibition of TRIF signaling. Our findings provide a novel mechanism for negative regulation of TRIF-mediated signaling.