m 6 A modification controls the innate immune response to infection by targeting type I interferons

Nat Immunol. 2019 Feb;20(2):173-182. doi: 10.1038/s41590-018-0275-z. Epub 2018 Dec 17.

Abstract

N6-methyladenosine (m6A) is the most common mRNA modification. Recent studies have revealed that depletion of m6A machinery leads to alterations in the propagation of diverse viruses. These effects were proposed to be mediated through dysregulated methylation of viral RNA. Here we show that following viral infection or stimulation of cells with an inactivated virus, deletion of the m6A 'writer' METTL3 or 'reader' YTHDF2 led to an increase in the induction of interferon-stimulated genes. Consequently, propagation of different viruses was suppressed in an interferon-signaling-dependent manner. Significantly, the mRNA of IFNB, the gene encoding the main cytokine that drives the type I interferon response, was m6A modified and was stabilized following repression of METTL3 or YTHDF2. Furthermore, we show that m6A-mediated regulation of interferon genes was conserved in mice. Together, our findings uncover the role m6A serves as a negative regulator of interferon response by dictating the fast turnover of interferon mRNAs and consequently facilitating viral propagation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine / analogs & derivatives*
  • Adenosine / metabolism
  • Animals
  • Cell Line, Tumor
  • Cytomegalovirus / immunology
  • Disease Models, Animal
  • Female
  • Fibroblasts
  • Herpesviridae Infections / immunology
  • Herpesviridae Infections / virology
  • Host-Pathogen Interactions / genetics*
  • Host-Pathogen Interactions / immunology
  • Humans
  • Immunity, Innate / genetics*
  • Influenza A Virus, H1N1 Subtype / immunology
  • Influenza, Human / immunology
  • Influenza, Human / virology
  • Interferon Type I / genetics*
  • Interferon Type I / immunology
  • Male
  • Methylation
  • Methyltransferases / genetics
  • Methyltransferases / immunology
  • Methyltransferases / metabolism
  • Mice
  • Mice, Inbred ICR
  • Mice, Knockout
  • Muromegalovirus / immunology
  • RNA, Messenger / metabolism*
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / immunology
  • RNA-Binding Proteins / metabolism

Substances

  • Interferon Type I
  • RNA, Messenger
  • RNA-Binding Proteins
  • YTHDF2 protein, human
  • YTHDF2 protein, mouse
  • N6-methyladenosine (m6A)
  • Methyltransferases
  • Mettl3 protein, mouse
  • METTL3 protein, human
  • Adenosine