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

Research output: Contribution to journalArticle

396 Scopus citations

Abstract

Cellular messenger RNA (mRNA) of higher eukaryotes and many viral RNAs are methylated at the N-7 and 2′O positions of the 5-2 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 5-2 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.

Original languageEnglish (US)
Pages (from-to)452-456
Number of pages5
JournalNature
Volume468
Issue number7322
DOIs
StatePublished - Nov 18 2010
Externally publishedYes

ASJC Scopus subject areas

  • General

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    Daffis, S., Szretter, K. J., Schriewer, J., Li, J., Youn, S., Errett, J., Lin, T. Y., Schneller, S., Zust, R., Dong, H., Thiel, V., Sen, G. C., Fensterl, V., Klimstra, W. B., Pierson, T. C., Buller, R. M., Gale Jr, M., Shi, P. Y., & Diamond, M. S. (2010). 2′-O methylation of the viral mRNA cap evades host restriction by IFIT family members. Nature, 468(7322), 452-456. https://doi.org/10.1038/nature09489