RIP1 is an essential mediator of Toll-like receptor 3-induced NF-κB activation
RIP1 is an essential mediator of Toll-like receptor 3-induced NF-κB activation
复制标题
DOI：
10.1038/ni1061
复制
发表时间：
2004-05-01
影响因子：
30.5
通讯作者：
Tschopp, J
中科院分区：
文献类型：
--
作者：
Meylan, E;Burns, K;Tschopp, J
Toll 样受体 (TLR) 的刺激可通过含有 Toll-白细胞介素 1 受体 (TIR) 结构域的接头（例如 MyD88 和 Trif）启动有效的先天免疫反应。对 Trif 缺陷小鼠的分析表明，TLR3 配体双链 RNA 对转录因子 NF-kappaB 的 TLR3 依赖性激活是 Trif 依赖性的。在这里，我们研究了调节 TLR3 依赖性 Trif 诱导的 NF-kappaB 激活的“下游”信号事件。 Trif 通过其 RIP 同型相互作用基序招募激酶受体相互作用蛋白 (RIP)-1 和 RIP3。在 RIP1 缺失的情况下，TLR3 介导的激活 NF-kappaB 的信号被消除，但激酶 JNK 或干扰素-β 并未被消除，这表明 RIP1 介导 Trif 诱导的 NF-kappaB 激活。相反，RIP3 的存在对 Trif-RIP1 诱导的 NF-kappaB 通路产生负调节。因此，与其他使用白介素 1 受体相关激酶 (IRAK) 蛋白激活 NF-kappaB 的 TLR 不同，TLR 3 诱导的 NF-kappaB 激活依赖于 RIP 激酶。
Stimulation of Toll-like receptors (TLRs) initiates potent innate immune responses through Toll-interleukin 1 receptor (TIR) domain-containing adaptors such as MyD88 and Trif. Analysis of Trif-deficient mice has shown that TLR3-dependent activation of the transcription factor NF-kappaB by the TLR3 ligand double-stranded RNA is Trif dependent. Here we investigated the 'downstream' signaling events that regulate TLR3-dependent Trif-induced NF-kappaB activation. Trif recruited the kinases receptor interacting protein(RIP)-1 and RIP3 through its RIP homotypic interaction motif. In the absence of RIP1, TLR3-mediated signals activating NF-kappaB, but not the kinase JNK or interferon-beta,were abolished, suggesting that RIP1 mediates Trif-induced NF-kappaB activation. In contrast, the presence of RIP3 negatively regulated the Trif-RIP1-induced NF-kappaB pathway. Therefore, in contrast to other TLRs, which use interleukin 1 receptor-associated kinase (IRAK) proteins to activate NF-kappaB, TLR 3-induced NF-kappaB activation is dependent on RIP kinases.