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

Ronit 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

Ronit 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

Weizmann Institute of Science, Tel Aviv University

Research output: Contribution to journal › Article › peer-review

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 cxgenes 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.

Original language	English
Pages (from-to)	173-182
Number of pages	10
Journal	Nature Immunology
Volume	20
Issue number	2
Early online date	17 Dec 2018
DOIs	https://doi.org/10.1038/s41590-018-0275-z
State	Published - 1 Feb 2019

All Science Journal Classification (ASJC) codes

Immunology and Allergy
Immunology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41590-018-0275-z

ss_NatImmun_M6AModificationControls_AM2018Accepted author manuscript, 14.9 MB

Cite this

Winkler, R., Gillis, E., Lasman, L., Safra, M., Geula, S., Soyris, C., Nachshon, A., Tai-Schmiedel, J., Friedman, N., Le-Trilling, V. T. K., Trilling, M., Mandelboim, M., Hanna, J. H., Schwartz, S., & Stern-Ginossar, N. (2019). m⁶A modification controls the innate immune response to infection by targeting type I interferons. Nature Immunology, 20(2), 173-182. https://doi.org/10.1038/s41590-018-0275-z

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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 {\textquoteleft}writer{\textquoteright} METTL3 or {\textquoteleft}reader{\textquoteright} 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 cxgenes 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.",

author = "Ronit Winkler and Ella Gillis and Lior Lasman and Modi Safra and Shay Geula and Clara Soyris and Aharon Nachshon and Julie Tai-Schmiedel and Nehemya Friedman and Le-Trilling, {Vu Thuy Khanh} and Mirko Trilling and Michal Mandelboim and Hanna, {Jacob H.} and Schraga Schwartz and Noam Stern-Ginossar",

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Winkler, R, Gillis, E, Lasman, L, Safra, M, Geula, S, Soyris, C, Nachshon, A, Tai-Schmiedel, J, Friedman, N, Le-Trilling, VTK, Trilling, M, Mandelboim, M, Hanna, JH , Schwartz, S & Stern-Ginossar, N 2019, 'm⁶A modification controls the innate immune response to infection by targeting type I interferons', Nature Immunology, vol. 20, no. 2, pp. 173-182. https://doi.org/10.1038/s41590-018-0275-z

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T1 - m6A modification controls the innate immune response to infection by targeting type I interferons

AU - Winkler, Ronit

AU - Gillis, Ella

AU - Lasman, Lior

AU - Safra, Modi

AU - Geula, Shay

AU - Soyris, Clara

AU - Nachshon, Aharon

AU - Tai-Schmiedel, Julie

AU - Friedman, Nehemya

AU - Le-Trilling, Vu Thuy Khanh

AU - Trilling, Mirko

AU - Mandelboim, Michal

AU - Hanna, Jacob H.

AU - Schwartz, Schraga

AU - Stern-Ginossar, Noam

PY - 2019/2/1

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N2 - 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 cxgenes 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.

AB - 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 cxgenes 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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