2. Academic Validation
  3. m6A modification controls the innate immune response to infection by targeting type I interferons

m6A 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.
Roni Winkler 1,  Ella Gillis 1,  Lior Lasman 1,  Modi Safra 1,  Shay Geula 1,  Clara Soyris 1,  Aharon Nachshon 1,  Julie Tai-Schmiedel 1,  Nehemya Friedman 2 3,  Vu Thuy Khanh Le-Trilling 4,  Mirko Trilling 4,  Michal Mandelboim 2 3,  Jacob H Hanna 1,  Schraga Schwartz 1,  Noam Stern-Ginossar 5
Affiliations

Affiliations

  • 1 Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
  • 2 Central Virology Laboratory, Ministry of Health, Chaim Sheba Medical Center, Ramat-Gan, Israel.
  • 3 Department of Epidemiology and Preventive Medicine, School of Public Health, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
  • 4 Institut für Virologie, Universitätsklinikum Essen, Universität Duisburg-Essen, Essen, Germany.
  • 5 Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel. [email protected].
PMID: 30559377 DOI: 10.1038/s41590-018-0275-z
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.

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