Cleavage of the Adaptor Protein TRIF by Enterovirus 71 3C Inhibits Antiviral Responses Mediated by Toll-Like Receptor 3
Cleavage of the Adaptor Protein TRIF by Enterovirus 71 3C Inhibits Antiviral Responses Mediated by Toll-Like Receptor 3
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DOI：
10.1128/jvi.00447-11
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发表时间：
2011-09-01
影响因子：
5.4
通讯作者：
Wang, Jianwei
中科院分区：
文献类型：
--
作者：
Lei, Xiaobo;Sun, Zhenmin;Wang, Jianwei
肠道病毒71型（EV 71）可引起幼儿手足口病和神经系统并发症。尽管其潜在机制仍不清楚，但免疫功能受损或异常被认为起作用。在感染细胞中，EV 71抑制由维甲酸诱导基因I（RIG-I）介导的I型干扰素应答。这涉及EV 71 3C蛋白，其破坏功能性RIG-I复合物的形成。在本研究中，我们报告EV 71通过一种独特的机制抑制Toll样受体3（TLR 3）诱导的先天免疫。在HeLa细胞刺激与聚（I中心点C），EV 71失活干扰素调节因子3，并大大抑制干扰素刺激的基因表达。值得注意的是，EV 71特异性下调TRIF，含有TIR结构域的衔接子诱导β干扰素（IFN-β）。当在哺乳动物细胞中单独表达时，EV 71 3C能够表现出这些活性。EV 71 3C在半胱天冬酶抑制剂Z-VAD-FMK存在下与TRIF结合并诱导TRIF切割。TRIF切割依赖于其氨基酸对Q312-S313，其类似于小核糖核酸病毒3C蛋白酶的蛋白水解位点。此外，具有缺陷蛋白酶活性的位点特异性3C突变体结合TRIF，但不能介导TRIF切割。因此，这些3C突变体不能抑制NF-κ B和IFN-β启动子激活。由EV 71介导的TRIF切割可能是响应于Toll样受体3（TLR 3）活化而损害I型IFN产生的机制。
Enterovirus 71 (EV71) causes hand-foot-and-mouth disease and neurological complications in young children. Although the underlying mechanisms remain obscure, impaired or aberrant immunity is thought to play a role. In infected cells, EV71 suppresses type I interferon responses mediated by retinoid acid-inducible gene I (RIG-I). This involves the EV71 3C protein, which disrupts the formation of a functional RIG-I complex. In the present study, we report that EV71 inhibits the induction of innate immunity by Toll-like receptor 3 (TLR3) via a distinct mechanism. In HeLa cells stimulated with poly(I center dot C), EV71 inactivates interferon regulatory factor 3 and drastically suppresses interferon-stimulated gene expression. Notably, EV71 specifically down-regulates a TRIF, TIR domain-containing adaptor inducing beta interferon (IFN-beta). When expressed alone in mammalian cells, EV71 3C is capable of exhibiting these activities. EV71 3C associates with and induces TRIF cleavage in the presence of Z-VAD-FMK, a caspase inhibitor. TRIF cleavage depends on its amino acid pair Q312-S313, which resembles a proteolytic site of picornavirus 3C proteases. Further, site-specific 3C mutants with a defective protease activity bind TRIF but fail to mediate TRIF cleavage. Consequently, these 3C mutants are unable to inhibit NF-kappa B and IFN-beta promoter activation. TRIF cleavage mediated by EV71 may be a mechanism to impair type I IFN production in response to Toll-like receptor 3 (TLR3) activation.