FIG 10.

Model for how m⁶A methylation invades host innate immunity in NNS RNA viruses. The newly synthesized genome and antigenome of NNS RNA viruses are first methylated by m⁶A writer proteins, which are encapsidated by N protein to serve as a template for replication and transcription. Some of the genome and antigenome may not be encapsidated at an early stage in the virus replication cycle, particularly when the concentration of N protein is low. These unmodified antigenomes or genomes would be recognized by RIG-I to induce the IFN signaling pathway. m⁶A methylation in genome and antigenome prevents RIG-I binding, conformational change, oligomerization, and K63-linked polyubiquitination, which result in lower activation of MAVS and subsequent phosphorylation of IRF3, thereby inhibiting type I IFN production. In addition, YTHDF2 binds to the m⁶A-methylated genome and antigenome, which suppresses type I IFN signaling.