MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China.
J Virol. 2013 Feb;87(3):1690-8. doi: 10.1128/JVI.01855-12. Epub 2012 Nov 21.
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.
肠道病毒 71 型（EV71）是一种正链 RNA 病毒，能够抑制先天免疫。在病毒编码的蛋白中，3C 蛋白破坏了视黄酸诱导基因-I（RIG-I）或 Toll 样受体 3 介导的 I 型干扰素（IFN-I）反应，从而激活干扰素调节因子 3（IRF3）和 IRF7。在本研究中，我们报告肠道病毒 71 型通过 3C 蛋白下调 IRF7，从而抑制 IRF7 的功能。在哺乳动物细胞中表达时，3C 蛋白介导 IRF7 的切割而不是 IRF3 的切割。这一过程对 caspase、蛋白酶体、溶酶体和自噬抑制剂不敏感。3C 活性位点中的 H40D 取代使其活性丧失，而 RNA 结合基序中的 R84Q 或 V154S 取代则没有影响。此外，3C 介导的切割发生在 IRF7 固有激活域中的 Q189-S190 连接处，导致两个无法激活 IFN 表达的切割 IRF7 片段。野生型 IRF7 的异位表达限制了 EV71 的复制。另一方面，IRF7 氨基末端结构域的表达增强了 EV71 感染，这与其与 IRF3 相互作用和抑制 IRF3 的能力相关。这些结果表明，3C 蛋白对 IRF7 的控制可能代表病毒逃避细胞反应的一种机制。
