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- Title
2′-O methylation of the viral mRNA cap evades host restriction by IFIT family members.
- 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 Jr, Michael; Shi, Pei-Yong; Diamond, Michael S.
- 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.
- Subjects
MESSENGER RNA; METHYLATION; CYTOGENETICS; GUANOSINE triphosphatase; METHYLTRANSFERASES; WEST Nile virus; INTERFERONS
- Publication
Nature, 2010, Vol 468, Issue 7322, p452
- ISSN
0028-0836
- Publication type
Article
- DOI
10.1038/nature09489