Degradation of WTAP blocks antiviral responses by reducing the m6 A levels of IRF3 and IFNAR1 mRNA.

ABSTRACT

N6 -methyladenosine (m6 A) is a chemical modification present in multiple RNA species and is most abundant in mRNAs. Studies on m6 A reveal its comprehensive roles in almost every aspect of mRNA metabolism, as well as in a variety of physiological processes. Although some recent discoveries indicate that m6 A can affect the life cycles of numerous viruses as well as the cellular antiviral immune response, the roles of m6 A modification in type I interferon (IFN-I) signaling are still largely unknown. Here, we reveal that WT1-associated protein (WTAP), one of the m6 A "writers", is degraded via the ubiquitination-proteasome pathway upon activation of IFN-I signaling. With the degradation of WTAP, the m6 A levels of IFN-regulatory factor 3 (IRF3) and interferon alpha/beta receptor subunit 1 (IFNAR1) mRNAs are reduced, leading to translational suppression of IRF3 and instability of IFNAR1 mRNA. Thus, the WTAP-IRF3/IFNAR1 axis may serve as negative feedback pathway to fine-tune the activation of IFN-I signaling, which highlights the roles of m6 A in the antiviral response by dictating the fate of mRNAs associated with IFN-I signaling.