Cleavage of Interferon Regulatory Factor 7 by Enterovirus 71 3C Suppresses Cellular Responses
Cleavage of Interferon Regulatory Factor 7 by Enterovirus 71 3C Suppresses Cellular Responses
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肠道病毒 71 3C 裂解干扰素调节因子 7 抑制细胞反应
DOI：
10.1128/jvi.01855-12
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发表时间：
2013-02-01
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;Xiao, Xia;Wang, Jianwei
肠道病毒71型（EV 71）是一种能抑制先天性免疫的正链RNA病毒。在病毒编码的蛋白质中，3C蛋白损害由类视黄酸诱导基因-I（RIG-I）或Toll样受体3介导的I型干扰素（IFN-I）应答，所述Toll样受体3激活干扰素调节3（IRF 3）和IRF 7。在本研究中，我们报告肠道病毒71型通过3C蛋白下调IRF 7，从而抑制IRF 7的功能。当在哺乳动物细胞中表达时，3C蛋白介导IRF 7而不是IRF 3的切割。该过程对胱天蛋白酶、蛋白酶体、溶酶体和自噬的抑制剂不敏感。3C活性位点中的H40 D取代废除了其活性，而RNA结合基序中的R84 Q或V154 S取代没有影响。此外，3C介导的切割发生在IRF 7组成型激活结构域内的Q189-S190接合处，产生两个无法激活IFN表达的切割IRF 7片段。野生型IRF 7的异位表达限制EV 71复制。另一方面，IRF 7的氨基末端结构域的表达增强EV 71感染，这与其与IRF 3相互作用并抑制IRF 3的能力相关。这些结果表明，3C蛋白对IRF 7的控制可能代表了逃避细胞反应的病毒机制。
ABSTRACT Enterovirus 71 (EV71) is a positive-stranded RNA virus which is capable of inhibiting innate immunity. Among virus-encoded proteins, the 3C protein compromises the type I interferon (IFN-I) response mediated by retinoid acid-inducible gene-I (RIG-I) or Toll-like receptor 3 that activates interferon regulatory 3 (IRF3) and IRF7. In the present study, we report that enterovirus 71 downregulates IRF7 through the 3C protein, which inhibits the function of IRF7. When expressed in mammalian cells, the 3C protein mediates cleavage of IRF7 rather than that of IRF3. This process is insensitive to inhibitors of caspase, proteasome, lysosome, and autophagy. H40D substitution in the 3C active site abolishes its activity, whereas R84Q or V154S substitution in the RNA binding motif has no effect. Furthermore, 3C-mediated cleavage occurs at the Q189-S190 junction within the constitutive activation domain of IRF7, resulting in two cleaved IRF7 fragments that are incapable of activating IFN expression. Ectopic expression of wild-type IRF7 limits EV71 replication. On the other hand, expression of the amino-terminal domain of IRF7 enhances EV71 infection, which correlates with its ability to interact with and inhibit IRF3. These results suggest that control of IRF7 by the 3C protein may represent a viral mechanism to escape cellular responses.