State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China; State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, China; Laboratory of RNA Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, Hubei 430071, China.
State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, China.
Immunity. 2017 Jun 20;46(6):992-1004.e5. doi: 10.1016/j.immuni.2017.05.006.
RNA interference (RNAi) functions as a potent antiviral immunity in plants and invertebrates; however, whether RNAi plays antiviral roles in mammals remains unclear. Here, using human enterovirus 71 (HEV71) as a model, we showed HEV71 3A protein as an authentic viral suppressor of RNAi during viral infection. When the 3A-mediated RNAi suppression was impaired, the mutant HEV71 readily triggered the production of abundant HEV71-derived small RNAs with canonical siRNA properties in cells and mice. These virus-derived siRNAs were produced from viral dsRNA replicative intermediates in a Dicer-dependent manner and loaded into AGO, and they were fully active in degrading cognate viral RNAs. Recombinant HEV71 deficient in 3A-mediated RNAi suppression was significantly restricted in human somatic cells and mice, whereas Dicer deficiency rescued HEV71 infection independently of type I interferon response. Thus, RNAi can function as an antiviral immunity, which is induced and suppressed by a human virus, in mammals.
RNA 干扰 (RNAi) 在植物和无脊椎动物中作为一种有效的抗病毒免疫机制发挥作用；然而，RNAi 是否在哺乳动物中发挥抗病毒作用尚不清楚。在这里，我们使用人类肠道病毒 71 型 (HEV71) 作为模型，表明 HEV71 3A 蛋白在病毒感染过程中是一种真正的病毒 RNAi 抑制因子。当 3A 介导的 RNAi 抑制作用受损时，突变的 HEV71 容易在细胞和小鼠中引发大量具有典型 siRNA 特性的 HEV71 衍生小 RNA 的产生。这些病毒衍生的 siRNA 是通过 Dicer 依赖性方式从病毒 dsRNA 复制中间体产生的，并装载到 AGO 中，它们在降解同源病毒 RNA 方面完全有效。缺乏 3A 介导的 RNAi 抑制的重组 HEV71 在人体细胞和小鼠中受到明显限制，而 Dicer 缺陷独立于 I 型干扰素反应挽救了 HEV71 感染。因此，RNAi 可以作为一种抗病毒免疫机制在哺乳动物中发挥作用，而这种免疫机制是由人类病毒诱导和抑制的。
