2'-O methylation of the viral mRNA cap evades host restriction by IFIT family members.
2'-O methylation of the viral mRNA cap evades host restriction by IFIT family members.
复制标题
病毒mRNA帽的2'-O甲基化通过IFIT家族成员逃避了宿主的限制。
作者：
许多细胞信使RNA和病毒RNA在5′鸟苷帽的2′-O位置被甲基化。这种修饰在病毒感染中的作用尚不清楚。Michael Diamond及其同事现在表明，这种形式的甲基化使几种不相关的病毒能够通过逃避干扰素刺激基因的抑制来逃避先天宿主抗病毒反应。这为细胞mRNA的2′-O甲基化提供了进化上的解释：它可以在感染条件下区分自身和非自身RNA。特异性抑制细胞质病毒2′-O甲基转移酶的新型药物可能具有广谱抗病毒活性。本文的在线版本（doi：10.1038/nature 09489）包含补充材料，可供授权用户使用。许多细胞和病毒信使RNA在5′鸟苷帽的2′-O位置被甲基化。2′-O甲基化在病毒感染中的作用尚不清楚。这些作者表明，这种形式的甲基化使几种不相关的病毒能够逃避I型干扰素刺激的基因的抗病毒作用。本文的在线版本（doi：10.1038/nature 09489）包含补充材料，可供授权用户使用。高等真核生物和许多病毒RNA的细胞信使RNA（mRNA）在5′鸟苷帽的N-7和2′-O位置分别被特异性的细胞核和细胞质甲基转移酶（MTases）甲基化。尽管N-7甲基化对RNA的翻译和稳定性至关重要，但自35年前发现以来，2′-O甲基化的功能仍然不确定。在这里，我们表明，西尼罗河病毒（WNV）突变体（E218 A），缺乏2′-O MTase活性的野生型原代细胞和小鼠中减毒，但在缺乏I型干扰素（IFN）信号转导的致病性。在WNV感染的成纤维细胞中，病毒RNA的2′-O甲基化不影响IFN诱导，而是通过三肽重复序列（IFIT）调节IFN诱导蛋白的抗病毒作用，IFIT是干扰素刺激的基因（ISG），参与蛋白质翻译的调节。缺乏2′-O MTase活性的痘病毒和冠状病毒突变体同样显示出对IFN，特别是IFIT蛋白的抗病毒作用的敏感性增强。我们的研究结果表明，2′-O甲基化的5′帽病毒RNA的功能，破坏先天宿主的抗病毒反应，通过逃避IFIT介导的抑制，并提出了一个进化的解释细胞mRNA的2′-O甲基化：区分自我和非自我RNA。细胞质RNA的差异甲基化可能是模式识别和限制外源病毒RNA在宿主细胞中繁殖的一个例子。本文的在线版本（doi：10.1038/nature 09489）包含补充材料，可供授权用户使用。
Many cellular messenger RNAs and viral RNAs are methylated at the 2′-O position of the 5′ guanosine cap. The role of this modification in virus infection has been unclear. Michael Diamond and colleagues now show that this form of methylation enables several unrelated viruses to evade innate host antiviral responses through escape from suppression by interferon-stimulated genes. This suggests an evolutionary explanation for 2′-O methylation of cellular mRNA: it may distinguish self from non-self RNA under conditions of infection. Novel classes of pharmacological agents that specifically inhibit cytoplasmic viral 2′-O methyltransferases may be expected to have broad-spectrum antiviral activity. The online version of this article (doi:10.1038/nature09489) contains supplementary material, which is available to authorized users. Many cellular and virus messenger RNAs are methylated at the 2′-O positions of the 5′ guanosine cap. The role of 2′-O methylation in virus infection has been unclear. These authors show that this form of methylation enables several unrelated viruses to evade the antiviral effects of genes stimulated by type I interferon. The online version of this article (doi:10.1038/nature09489) contains supplementary material, which is available to authorized users. Cellular messenger RNA (mRNA) of higher eukaryotes and many viral RNAs are methylated at the N-7 and 2′-O positions of the 5′ guanosine cap by specific nuclear and cytoplasmic methyltransferases (MTases), respectively. Whereas N-7 methylation is essential for RNA translation and stability, the function of 2′-O methylation has remained uncertain since its discovery 35 years ago. Here we show that a West Nile virus (WNV) mutant (E218A) that lacks 2′-O MTase activity was attenuated in wild-type primary cells and mice but was pathogenic in the absence of type I interferon (IFN) signalling. 2′-O methylation of viral RNA did not affect IFN induction in WNV-infected fibroblasts but instead modulated the antiviral effects of IFN-induced proteins with tetratricopeptide repeats (IFIT), which are interferon-stimulated genes (ISGs) implicated in regulation of protein translation. Poxvirus and coronavirus mutants that lacked 2′-O MTase activity similarly showed enhanced sensitivity to the antiviral actions of IFN and, specifically, IFIT proteins. Our results demonstrate that the 2′-O methylation of the 5′ cap of viral RNA functions to subvert innate host antiviral responses through escape of IFIT-mediated suppression, and suggest an evolutionary explanation for 2′-O methylation of cellular mRNA: to distinguish self from non-self RNA. Differential methylation of cytoplasmic RNA probably serves as an example for pattern recognition and restriction of propagation of foreign viral RNA in host cells. The online version of this article (doi:10.1038/nature09489) contains supplementary material, which is available to authorized users.
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影响因子：
3.7
作者：
Latner, DR;Thompson, JM;Condit, RC
通讯作者：
Condit, RC
影响因子：
5.4
作者：
Samuel, MA;Diamond, MS
通讯作者：
Diamond, MS
影响因子：
5.4
作者：
Wacher, Christie;Muller, Marcus;Campbell, Iain L.
通讯作者：
Campbell, Iain L.
DOI：
10.1073/pnas.72.1.318
发表时间：
1975-01-01
影响因子：
11.1
作者：
WEI, CM;MOSS, B
通讯作者：
MOSS, B
影响因子：
5.4
作者：
Zhang, Yugen;Burke, Crystal W.;Klimstra, William B.
通讯作者：
Klimstra, William B.