NAK-associated protein 1 participates in both the TLR3 and the cytoplasmic pathways in type IIFN induction
NAK-associated protein 1 participates in both the TLR3 and the cytoplasmic pathways in type IIFN induction
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DOI：
10.4049/jimmunol.177.12.8676
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发表时间：
2006-12-15
影响因子：
4.4
通讯作者：
Seya, Tsukasa
中科院分区：
文献类型：
--
作者：
Sasai, Miwa;Shingai, Masashi;Seya, Tsukasa
TLR3 和细胞质解旋酶家族蛋白（视黄酸诱导基因 I (RIG-I) 和黑色素瘤分化相关基因 5 (MDA5)）充当 dsRNA 模式识别受体。响应于 dsRNA 的代表 Poly(I:C) 和病毒感染，它们已被证明可以激活转录因子 IFN 调节因子 (IRF)-3，进而诱导 IFN-β 启动子的激活。 RIG-I/MDA5 识别细胞质中的 dsRNA，而 TLR3 驻留在细胞表面膜或内体中，参与 dsRNA 的胞质外识别。最近的报告表明，TLR3 诱导上皮细胞响应呼吸道合胞病毒 (RSV) 的细胞反应。然而，RSV 激活 TLR3 的方式仍未解决。通过小干扰RNA基因沉默技术和人细胞转染子，我们发现NAK相关蛋白1（NAP1）的敲低会导致在poly（I：Q或病毒（RSV和水泡性口炎病毒）处理后> 24小时内IFN-β启动子激活下调。NAP1位于含有Toll-IL-1R同源结构域的接头下游 TLR3 途径中存在接头分子 (TICAM)-1（含有 Toll/IL-IR 结构域的接头诱导 IFN-β），但 TICAM-1 和 TLR3 不参与 RSV 感染引起的 IRF-3 和 IFN-β 启动子激活。病毒介导的 IFN-β 启动子激活在很大程度上被 IFN-β 基因沉默所消除。 IFN-β 启动子刺激物-1（线粒体抗病毒信号传导 (MAVS)、VISA、Cardif），RIG-I/MDA5 dsRNA 识别蛋白的接头。在 TLR 和病毒介导的 IFN 诱导途径中，I kappa B 激酶相关激酶 epsilon 和 TANK 结合激酶 I 参与 IFN-beta 感应。因此，RSV以及其他病毒诱导复制介导的IFN-β启动子激活，这是由RIG-I/MDA5而不是TLR3途径在细胞内启动的。细胞质和 TLR3 介导的 dsRNA 识别途径均汇聚于 NAP1，以激活 IRF-3 和 IFN-β 启动子。
TLR3 and the cytoplasmic helicase family proteins (retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5)) serve as dsRNA pattern-recognition receptors. In response to poly(I:C), a representative of dsRNA, and viral infection, they have been shown to activate the transcription factor IFN regulatory factor (IRF)-3, which in turn induces activation of the IFN-beta promoter. RIG-I/MDA5 recognizes dsRNA in the cytoplasm, whereas TLR3 resides in the cell surface membrane or endosomes to engage in extracytoplasmic recognition of dsRNA. Recent reports suggest that TLR3 induces cellular responses in epithelial cells in response to respiratory syncytial virus (RSV). The modus for TLR3 activation by RSV, however, remains unresolved. By small interference RNA gene-silencing technology and human cell transfectants, we have revealed that knockdown of NAK-associated protein 1 (NAP1) leads to the down-regulation of IFN-beta promoter activation > 24 h after poly(I:Q or virus (RSV and vesicular stomatitis virus) treatment. NAP1 is located downstream of the adapter Toll-IL-1R homology domain-containing adapter molecule (TICAM)-1 (Toll/IL-IR domain-containing adapter-inducing IFN-beta) in the TLR3 pathway, but TICAM-1 and TLR3 did not participate in the IRF-3 and IFN-beta promoter activation by RSV infection. Virus-mediated activation of the IFN-beta promoter was largely abrogated by the gene silencing of IFN-beta promoter stimulator-1 (mitochondria antiviral signaling (MAVS), VISA, Cardif), the adapter of the RIG-I/MDA5 dsRNA-recognition proteins. In both the TLR and virus-mediated IFN-inducing pathways, I kappa B kinase-related kinase epsilon and TANK-binding kinase I participated in IFN-beta induction. Thus, RSV as well as other viruses induces replication-mediated activation of the IFN-beta promoter, which is intracellularly initiated by the RIG-I/MDA5 but not the TLR3 pathway. Both the cytoplasmic and TLR3-mediated dsRNA recognition pathways converge upon NAP1 for the activation of the IRF-3 and IFN-beta promoter.