2'-O Methylation of the Viral mRNA Cap Evades Host Restriction by IFIT Family Members

Nature. 2010 Nov 18;468(7322):452-6. doi: 10.1038/nature09489.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells
  • Animals
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cells, Cultured
  • Coronavirus / enzymology
  • Coronavirus / genetics
  • Coronavirus / immunology
  • Coronavirus / physiology
  • Fibroblasts
  • Gene Expression Regulation / genetics
  • Gene Expression Regulation / immunology*
  • Humans
  • Immunity, Innate / genetics
  • Immunity, Innate / immunology*
  • Interferons / deficiency
  • Interferons / genetics
  • Interferons / immunology*
  • Methylation
  • Methyltransferases / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Models, Genetic
  • Models, Immunological
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism
  • Poxviridae / enzymology
  • Poxviridae / genetics
  • Poxviridae / immunology
  • Poxviridae / physiology
  • Protein Biosynthesis / immunology
  • Proteins / genetics
  • Proteins / metabolism*
  • RNA Caps / genetics
  • RNA Caps / immunology
  • RNA Caps / metabolism*
  • RNA, Viral / genetics
  • RNA, Viral / immunology
  • RNA, Viral / metabolism*
  • RNA-Binding Proteins
  • Receptor, Interferon alpha-beta / deficiency
  • Receptor, Interferon alpha-beta / genetics
  • Survival Rate
  • Virus Replication
  • West Nile virus / enzymology
  • West Nile virus / genetics
  • West Nile virus / immunology
  • West Nile virus / physiology

Substances

  • Carrier Proteins
  • IFIT5 protein, human
  • Ifit1 protein, mouse
  • Ifit2 protein, mouse
  • Ifnar1 protein, mouse
  • Neoplasm Proteins
  • Proteins
  • RNA Caps
  • RNA, Viral
  • RNA-Binding Proteins
  • Receptor, Interferon alpha-beta
  • Interferons
  • Methyltransferases