METTL3 regulates viral m6A RNA modification and host cell innate immune responses during SARS-CoV-2 infection

Cell Rep. 2021 May 11;35(6):109091. doi: 10.1016/j.celrep.2021.109091. Epub 2021 May 3.


It is urgent and important to understand the relationship of the widespread severe acute respiratory syndrome coronavirus clade 2 (SARS-CoV-2) with host immune response and study the underlining molecular mechanism. N6-methylation of adenosine (m6A) in RNA regulates many physiological and disease processes. Here, we investigate m6A modification of the SARS-CoV-2 gene in regulating the host cell innate immune response. Our data show that the SARS-CoV-2 virus has m6A modifications that are enriched in the 3' end of the viral genome. We find that depletion of the host cell m6A methyltransferase METTL3 decreases m6A levels in SARS-CoV-2 and host genes, and m6A reduction in viral RNA increases RIG-I binding and subsequently enhances the downstream innate immune signaling pathway and inflammatory gene expression. METTL3 expression is reduced and inflammatory genes are induced in patients with severe coronavirus disease 2019 (COVID-19). These findings will aid in the understanding of COVID-19 pathogenesis and the design of future studies regulating innate immunity for COVID-19 treatment.

Keywords: METTL3; RIG-I; SARS-CoV-2; host innate immunity; inflammation; m(6)A RNA modification.

Publication types

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

MeSH terms

  • Adenosine / metabolism
  • COVID-19 / genetics*
  • COVID-19 / metabolism
  • Cell Line
  • DEAD Box Protein 58 / genetics
  • DEAD Box Protein 58 / metabolism
  • Humans
  • Immunity, Innate / genetics
  • Methylation
  • Methyltransferases / genetics
  • Methyltransferases / metabolism*
  • RNA, Viral / genetics
  • Receptors, Immunologic / genetics
  • Receptors, Immunologic / metabolism
  • SARS-CoV-2 / genetics*
  • SARS-CoV-2 / pathogenicity
  • Signal Transduction


  • RNA, Viral
  • Receptors, Immunologic
  • 6-methyladenine mRNA methyltransferase
  • Methyltransferases
  • METTL3 protein, human
  • DDX58 protein, human
  • DEAD Box Protein 58
  • Adenosine