Post-Transcriptional Regulation of Antiviral Gene Expression byN6-Methyladenosine

Summary Type I interferons (IFN) induce hundreds of IFN-stimulated genes (ISGs) in response to viral infection. These ISGs require strict regulation for an efficient and controlled antiviral response, but post-transcriptional controls of these genes have not been well defined. Here, we identify a new role for the RNA base modification N6 -methyladenosine (m 6 A) in the regulation of ISGs. Using ribosome profiling and quantitative mass spectrometry, coupled with m 6 A-immunoprecipitation and sequencing, we identified a subset of ISGs, including IFITM1 , whose translation is enhanced by m 6 A and the m 6 A methyltransferase proteins METTL3 and METTL14. We further determined that the m 6 A reader YTHDF1 increases the expression of IFITM1 in an m 6 A binding-dependent manner. Importantly, we found that the m 6 A methyltransferase complex promotes the antiviral activity of type I IFN. Thus, these studies identify m 6 A as a post-transcriptional control of ISG translation during the type I IFN response for antiviral restriction.