2'-O methylation of the viral mRNA cap evades host restriction by IFIT family members |
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Authors: | Daffis Stephane Szretter Kristy J Schriewer Jill Li Jianqing Youn Soonjeon Errett John Lin Tsai-Yu Schneller Stewart Zust Roland Dong Hongping Thiel Volker Sen Ganes C Fensterl Volker Klimstra William B Pierson Theodore C Buller R Mark Gale Michael Shi Pei-Yong Diamond Michael S |
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Institution: | Department of Medicine, Washington University School of Medicine, St Louis, Missouri 63110, USA. |
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Abstract: | 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. |
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