N6-methyladenosine (m6A) RNA modifications control the antiviral response to influenza A virus infection by limiting IFITM2/3 expression
- 1King's College London
Abstract
N6-methyladenosine (m6A) RNA modifications regulate diverse cellular processes, including the response to virus infection. However, how m6A controls antiviral gene expression and whether effects on viral replication are due to direct modification of viral RNA or regulation of cellular transcripts remain unclear. Herein, we analysed how m6A modifications control the cell-autonomous innate immune response to influenza A virus (IAV) infection. Depletion or inhibition of the m6A writer METTL3 or the m6A reader YTHDF2 restricts IAV replication. However, using a quantitative method to identify m6A sites, we did not detect substantial m6A modification of viral RNA. In contrast, many IAV-induced cellular transcripts were m6A modified in their coding region, including those that encode pattern recognition receptors and direct antiviral proteins. Inhibition of interferon signalling restored IAV replication after METTL3 inhibition, highlighting that m6A controls the antiviral response to infection. METTL3 inhibition increased expression of the paralogous antiviral proteins IFITM2 and IFITM3, which were required for the antiviral activity of the METTL3 inhibitor. We propose that m6A modifications regulate the expression of antiviral proteins to limit the magnitude of their induction and balance antiviral activity with maintaining cellular homeostasis.
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BibTeX
@misc{kwiatkowski2026n6methyladenosine,
title = {{N6-methyladenosine (m6A) RNA modifications control the antiviral response to influenza A virus infection by limiting IFITM2/3 expression}},
author = {P. Kwiatkowski and L. A. Mikheeva and H. Digby and C. R. Bouton and H. Jones and S. J. Neil and M. L. Holland and C. M. Swanson},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.01.755989},
url = {https://www.biorxiv.org/content/10.64898/2026.10.01.755989v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - N6-methyladenosine (m6A) RNA modifications control the antiviral response to influenza A virus infection by limiting IFITM2/3 expression
AU - P. Kwiatkowski
AU - L. A. Mikheeva
AU - H. Digby
AU - C. R. Bouton
AU - H. Jones
AU - S. J. Neil
AU - M. L. Holland
AU - C. M. Swanson
PY - 2026
DA - 2026/10/01
PB - bioRxiv
DO - 10.64898/2026.10.01.755989
UR - https://www.biorxiv.org/content/10.64898/2026.10.01.755989v1
AB - N6-methyladenosine (m6A) RNA modifications regulate diverse cellular processes, including the response to virus infection. However, how m6A controls antiviral gene expression and whether effects on viral replication are due to direct modification of viral RNA or regulation of cellular transcripts remain unclear. Herein, we analysed how m6A modifications control the cell-autonomous innate immune response to influenza A virus (IAV) infection. Depletion or inhibition of the m6A writer METTL3 or the m6A reader YTHDF2 restricts IAV replication. However, using a quantitative method to identify m6A sites, we did not detect substantial m6A modification of viral RNA. In contrast, many IAV-induced cellular transcripts were m6A modified in their coding region, including those that encode pattern recognition receptors and direct antiviral proteins. Inhibition of interferon signalling restored IAV replication after METTL3 inhibition, highlighting that m6A controls the antiviral response to infection. METTL3 inhibition increased expression of the paralogous antiviral proteins IFITM2 and IFITM3, which were required for the antiviral activity of the METTL3 inhibitor. We propose that m6A modifications regulate the expression of antiviral proteins to limit the magnitude of their induction and balance antiviral activity with maintaining cellular homeostasis.
ER -