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

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.