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N6-methyladenosine (m

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.

N 6‐methyladenosine (m6A) is a chemical modification present in multiple RNA species and is most abundant in mRNAs. Studies on m6A 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 m6A can affect the life cycles of numerous viruses as well as the cellular antiviral immune response, the roles of m6A modification in type I interferon (IFN‐I) signaling are still largely unknown. Here, we reveal that WT1‐associated protein (WTAP), one of the m6A “writers”, is degraded via the ubiquitination‐proteasome pathway upon activation of IFN‐I signaling. With the degradation of WTAP, the m6A 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 m6A in the antiviral response by dictating the fate of mRNAs associated with IFN‐I signaling., Proteasome mediated degradation of the m6A writer WTAP upon viral infection reduces m6A levels on IRF3 and IFNAR1 mRNAs and subsequently their protein output, thereby blocking IFN‐I‐mediated antiviral responses.