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

Open access
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.·2010·Nature

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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Metadata

Authors
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.
Venue
Nature
Published
2010-11-17
Volume
468
Issue
7322
Pages
452-456
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
OpenAlex
W2050843600
Cited by
907
References
23
FWCI
15.57
Type
journal article
Language
en
Open access
bronze

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CoChat. (2026). Citation check: 2′-O methylation of the viral mRNA cap evades host restriction by IFIT family members. https://app.cochat.ai/papers/10.1038/nature09489
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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. https://doi.org/10.1038/nature09489

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