Post-transcriptional regulation of antiviral gene expression by N6-methyladenosine

Type I interferons (IFNs) induce hundreds of IFN-stimulated genes (ISGs) in response to viral infection. Induction of these ISGs must be regulated for an efficient and controlled antiviral response, but post-transcriptional controls of these genes have not been well defined. Here, we identify a role for the RNA base modification N6-methyladenosine (m6A) in the regulation of ISGs. Using ribosome profiling and quantitative mass spectrometry, coupled with m6A-immunoprecipitation and sequencing, we identify a subset of ISGs, including IFITM1, whose translation is enhanced by m6A and the m6A methyltransferase proteins METTL3 and METTL14. We further determine that the m6A reader YTHDF1 increases the expression of IFITM1 in an m6A-binding-dependent manner. Importantly, we find that the m6A methyltransferase complex promotes the antiviral activity of type I IFN. Thus, these studies identify m6A as having a role in post-transcriptional control of ISG translation during the type I IFN response for antiviral restriction. [Display omitted] •During the type I IFN response, many IFN-stimulated genes (ISGs) are modified by m6A•m6A promotes the expression of a subset of these ISGs by enhancing their translation•m6A augments the antiviral effects of the type I interferon response McFadden et al. report that the transcripts of many interferon-stimulated genes (ISGs), which encode antiviral proteins, are m6A-modified. m6A promotes the translation of certain ISGs, enhancing the antiviral effects of interferon. This study adds to our understanding of the functions of m6A at the virus-host interface.