Elevated WTAP promotes hyperinflammation by increasing m6A modification in inflammatory disease models.

Emerging evidence has linked the dysregulation of N6-methyladenosine (m6A) modification to inflammation and inflammatory diseases, but the underlying mechanism still needs investigation. Here, we found that high levels of m6A modification in a variety of hyperinflammatory states are p65-dependent because Wilms tumor 1-associated protein (WTAP), a key component of the "writer" complex, is transcriptionally regulated by p65, and its overexpression can lead to increased levels of m6A modification. Mechanistically, upregulated WTAP is more prone to phase separation to facilitate the aggregation of the writer complex to nuclear speckles and the deposition of m6A marks on transcriptionally active inflammatory transcripts, thereby accelerating the proinflammatory response.

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

N -methyladenosine (m A) is a chemical modification present in multiple RNA species and is most abundant in mRNAs. Studies on m 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 m A can affect the life cycles of numerous viruses as well as the cellular antiviral immune response, the roles of m A modification in type I interferon (IFN-I) signaling are still largely unknown.