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

McFadden, Michael J.; McIntyre, Alexa B.R.; Mourelatos, Haralambos; Abell, Nathan S.; Gokhale, Nandan S.; Ipas, Hélène; Xhemalçe, Blerta; Mason, Christopher E.; Horner, Stacy M.

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 of these genes have not been well defined. Here, we identify a 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 identify 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 determine that the m(6)A reader YTHDF1 increases the expression of IFITM1 in an m(6)A-binding-dependent manner. Importantly, we find that the m(6)A methyltransferase complex promotes the antiviral activity of type I IFN. Thus, these studies identify m(6)A as having a role in post-transcriptional control of ISG translation during the type I IFN response for antiviral restriction.