RNA m 6 A modification enzymes shape innate responses to DNA by regulating interferon β

Genes Dev. 2018 Dec 1;32(23-24):1472-1484. doi: 10.1101/gad.319475.118. Epub 2018 Nov 21.

Abstract

Modification of mRNA by N 6-adenosine methylation (m6A) on internal bases influences gene expression in eukaryotes. How the dynamic genome-wide landscape of m6A-modified mRNAs impacts virus infection and host immune responses remains poorly understood. Here, we show that type I interferon (IFN) production triggered by dsDNA or human cytomegalovirus (HCMV) is controlled by the cellular m6A methyltrasferase subunit METTL14 and ALKBH5 demethylase. While METTL14 depletion reduced virus reproduction and stimulated dsDNA- or HCMV-induced IFNB1 mRNA accumulation, ALKBH5 depletion had the opposite effect. Depleting METTL14 increased both nascent IFNB1 mRNA production and stability in response to dsDNA. In contrast, ALKBH5 depletion reduced nascent IFNB1 mRNA production without detectably influencing IFN1B mRNA decay. Genome-wide transcriptome profiling following ALKBH5 depletion identified differentially expressed genes regulating antiviral immune responses, while METTL14 depletion altered pathways impacting metabolic reprogramming, stress responses, and aging. Finally, we determined that IFNB1 mRNA was m6A-modified within both the coding sequence and the 3' untranslated region (UTR). This establishes that the host m6A modification machinery controls IFNβ production triggered by HCMV or dsDNA. Moreover, it demonstrates that responses to nonmicrobial dsDNA in uninfected cells, which shape host immunity and contribute to autoimmune disease, are regulated by enzymes controlling m6A epitranscriptomic changes.

Keywords: RNA m6A modification; dsDNA signaling; human cytomegalovirus; innate immunity; virus infection.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • AlkB Homolog 5, RNA Demethylase / genetics
  • AlkB Homolog 5, RNA Demethylase / metabolism
  • Animals
  • Cell Line
  • Chlorocebus aethiops
  • Cytomegalovirus / immunology
  • DNA / immunology*
  • Gene Expression Profiling
  • Gene Expression Regulation / genetics*
  • Humans
  • Immune System / enzymology*
  • Immunity, Innate / genetics*
  • Interferon-beta / genetics*
  • Interferon-beta / metabolism
  • Methyltransferases / metabolism*
  • RNA Stability / genetics
  • Vero Cells
  • Virus Replication / genetics

Substances

  • Interferon-beta
  • DNA
  • AlkB Homolog 5, RNA Demethylase
  • METTL14 protein, human
  • Methyltransferases
  • METTL3 protein, human