Post-Transcriptional Regulation of Antiviral Gene Expression byN6-Methyladenosine

Abstract

SummaryType 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 (m6A) in the regulation of ISGs. Using ribosome profiling and quantitative mass spectrometry, coupled with m6A-immunoprecipitation and sequencing, we identified a subset of ISGs, including IFITM1, whose translation is enhanced by m6A and the m6A methyltransferase proteins METTL3 and METTL14. We further determined that the m6A reader YTHDF1 increases the expression of IFITM1 in an m6A binding-dependent manner. Importantly, we found that the m6A methyltransferase complex promotes the antiviral activity of type I IFN. Thus, these studies identify m6A as a post-transcriptional control of ISG translation during the type I IFN response for antiviral restriction.

Epitranscriptome profiling of spleen mRNA m6A methylation reveals pathways of host responses to malaria parasite infection

“…Representative read coverage plots were shown for Ifit2 (Figure 4C), this gene gained an obvious m 6 A peak in 3'UTR in N67CInfected samples and the expression level was dramatically upregulated by N67C infection (Figure 4B), consistent with the data that m 6 A enriched in 3'UTR had a positive effect on gene expression (Figure 3E). A recent study showed that the translation of interferon-induced genes could be enhanced after m 6 A modification as the antiviral mechanism (35). Thus, it is conceivable that m 6 A modification on these genes may have a similar role in the immune response to malaria infections.…”

N6-methyladenosine modification of viral RNA and its role during the recognition process of RIG-I-like receptors

“…promotes the production of interferon-stimulated genes (ISGs); however, Zhang's work indicated that YTHDF3 functions as a negative regulator of antiviral immunity by promoting the translation of FOXO3 mRNA (92, 93). METTL3, METTL14, and YTHDF1 promote the expression of interferon-induced transmembrane 1 (IFITM1), a well-known ISG (94). A recent study by You's group reported that m 6 A can stabilize IRF3 mRNA, and Zhu's group demonstrated that m 6 A can increase the stability of interferon-regulatory factor 7 (IRF7) mRNA (95,96).…”