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

Abstract

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.

Keywords: ISGs; Interferon; N6-methyladenosine; Translation; YTHDF1; m6A.