RNA Modifications Sculpt the Innate Immune Response to Infection

N⁶-methyladenosine (m⁶A) is the most common mRNA modification. Recent studies 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, the deletion of 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 main cytokine that drives type I interferon response, was m⁶A-modified, and was stabilized upon repression of METTL3 or YTHDF2. Furthermore, we show that m⁶A-mediated regulation of interferon genes was conserved in mouse. Altogether, our findings uncover the role of m⁶A as negative regulator of interferon response, by dictating the fast turnover of interferon mRNAs and consequently facilitating viral propagation.