Ribose 2'-O-methylation provides a molecular signature for the distinction of self and non-self mRNA dependent on the RNA sensor Mda5

Nat Immunol. 2011 Feb;12(2):137-43. doi: 10.1038/ni.1979. Epub 2011 Jan 9.

Abstract

The 5' cap structures of higher eukaryote mRNAs have ribose 2'-O-methylation. Likewise, many viruses that replicate in the cytoplasm of eukaryotes have evolved 2'-O-methyltransferases to autonomously modify their mRNAs. However, a defined biological role for 2'-O-methylation of mRNA remains elusive. Here we show that 2'-O-methylation of viral mRNA was critically involved in subverting the induction of type I interferon. We demonstrate that human and mouse coronavirus mutants lacking 2'-O-methyltransferase activity induced higher expression of type I interferon and were highly sensitive to type I interferon. Notably, the induction of type I interferon by viruses deficient in 2'-O-methyltransferase was dependent on the cytoplasmic RNA sensor Mda5. This link between Mda5-mediated sensing of viral RNA and 2'-O-methylation of mRNA suggests that RNA modifications such as 2'-O-methylation provide a molecular signature for the discrimination of self and non-self mRNA.

Publication types

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

MeSH terms

  • Animals
  • Cell Line
  • Coronavirus / pathogenicity
  • Coronavirus / physiology*
  • Coronavirus Infections / genetics
  • Coronavirus Infections / immunology
  • Coronavirus Infections / metabolism*
  • DEAD-box RNA Helicases / genetics
  • DEAD-box RNA Helicases / immunology
  • DEAD-box RNA Helicases / metabolism*
  • Humans
  • Immunity, Innate / genetics
  • Interferon Type I / genetics
  • Interferon Type I / immunology
  • Interferon Type I / metabolism
  • Interferon-Induced Helicase, IFIH1
  • Methylation
  • Methyltransferases / genetics
  • Methyltransferases / immunology
  • Methyltransferases / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • RNA, Viral / metabolism
  • Receptor, Interferon alpha-beta / genetics
  • Receptors, Pattern Recognition / genetics
  • Ribose / metabolism
  • Viral Proteins / genetics
  • Viral Proteins / immunology
  • Viral Proteins / metabolism*
  • Virulence / genetics
  • Virus Replication / genetics

Substances

  • Ifnar1 protein, mouse
  • Interferon Type I
  • RNA, Viral
  • Receptors, Pattern Recognition
  • Viral Proteins
  • Receptor, Interferon alpha-beta
  • Ribose
  • Methyltransferases
  • Ifih1 protein, mouse
  • DEAD-box RNA Helicases
  • Interferon-Induced Helicase, IFIH1