RNA MODIFICATIONS SCULPTS INNATE IMMUNE RESPONSE TO INFECTION

N6-methyladenosine (m6A) is the most common and abundant mRNA modification, and primarily leads to destabilization of modified transcripts. Recent studies revealed that depletion of m6A ‘writers’, ‘readers’ and ‘erasers’ leads to alterations in the life cycles of diverse DNA and RNA viruses. These effects were proposed to be mediated in a virus-specific manner, 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’ protein METTL3 or ‘reader’ protein YTHDF2 leads to a dramatic increase in the induction of hundreds of interferon-stimulated genes (ISGs), which constitutes the first line of antiviral defense. Consequently, propagation of different viruses is markedly suppressed in an interferon (IFN)-signaling dependent manner. Significantly, the mRNA of IFNβ, the central cytokine that drives the type I IFN response, is m6A modified, and is stabilized upon repression of METTL3 and YTHDF2. Furthermore, we show that m6A modification of IFNβ is conserved in mouse cells and that in vivo, after infection with murine cytomegalovirus, knockout mice lacking the m6A ‘reader’ protein YTHDF3 display enhanced IFNβ production. Altogether, our findings uncover the central role of m6A as negative regulator of type I IFN response, by dictating the fast turnover of IFNβ mRNA and consequently facilitating viral propagation. These findings suggest a potential parsimonious unifying model for interpreting the plethora of phenotypes associated with depletion of m6A and propagation of a variety of viruses.