m6A modification controls the innate immune response to infection by targeting type I interferons

Roni Winkler; Ella Gillis; Lior Lasman; Modi Safra; Shay Geula; Clara Soyris; Aharon Nachshon; Julie Tai-Schmiedel; Nehemya Friedman; Vu Thuy Khanh Le-Trilling; Mirko Trilling; Michal Mandelboim; Jacob H Hanna; Schraga Schwartz; Noam Stern-Ginossar

doi:10.1038/s41590-018-0275-z

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. Epub 2018 Dec 17.

Authors

Roni Winkler¹, Ella Gillis¹, Lior Lasman¹, Modi Safra¹, Shay Geula¹, Clara Soyris¹, Aharon Nachshon¹, Julie Tai-Schmiedel¹, Nehemya Friedman^{2

3}, Vu Thuy Khanh Le-Trilling⁴, Mirko Trilling⁴, Michal Mandelboim^{2

3}, Jacob H Hanna¹, Schraga Schwartz¹, Noam Stern-Ginossar⁵

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. noam.stern-ginossar@weizmann.ac.il.

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.

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
N-methyladenosine
Methyltransferases
Mettl3 protein, mouse
METTL3 protein, human
Adenosine