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Nature:逃避先天性宿主抗病毒反应的机制

2010/11/22 来源:Nature
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导读
很多细胞和病毒信使RNA是在5′鸟苷帽的2′-O位置被甲基化的。这种修饰在病毒感染中的作用一直不清楚。现在,Michael Diamond及其同事发现,这种形式的甲基化能使几种不相关的病毒通过逃避由干扰素刺激的基因所产生的抑制来逃避先天性宿主抗病毒反应。 这为细胞mRNA 的

很多细胞和病毒信使RNA是在5′鸟苷帽的2′-O位置被甲基化的。这种修饰在病毒感染中的作用一直不清楚。现在,Michael Diamond及其同事发现,这种形式的甲基化能使几种不相关的病毒通过逃避由干扰素刺激的基因所产生的抑制来逃避先天性宿主抗病毒反应。

这为细胞mRNA 的 2′-O端甲基化提出一个演化解释:它也许能够在感染条件下将自身RNA与非自身RNA区分开来。专门抑制胞质病毒2′-O端甲基转移酶的药理性试剂也许有广谱抗病毒活性。

 

英文摘要:

Nature doi:10.1038/nature09489

2′-O methylation of the viral mRNA cap evades host restriction by IFIT family members

Stephane Daffis,Kristy J. Szretter,Jill Schriewer,Jianqing Li,Soonjeon Youn,John Errett,Tsai-Yu Lin,Stewart Schneller,Roland Zust,Hongping Dong,Volker Thiel,Ganes C. Sen,Volker Fensterl,William B. Klimstra,Theodore C. Pierson,R. Mark Buller,Michael Gale Jr,Pei-Yong Shi" Michael S. Diamond

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 stability1, the function of 2′-O methylation has remained uncertain since its discovery 35 years ago2, 3, 4. 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.

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