N6-methyladenosine RNA modification suppresses antiviral innate sensing pathways via reshaping double-stranded RNA modules

Here we report that in response to the infection of RNA virus Vesicular Stomatitis Virus (VSV), the m6A methyltransferase METTL3 is largely translocated to cytoplasm. This behavior significantly increases the m6A modification on VSV positive-sense (+) RNAs to decrease their dsRNA loads, following impairs the sensing efficacy by RLRs, including RIG-I and MDA5, to globally suppress antiviral immune signaling cascades. With enhanced type I IFN expression in vivo, the genetic ablation of METTL3 in monocyte or hepatocyte accelerates viral clearance to VSV exposure. Our findings reveal that METTL3-mediated m6A RNA modification on VSV (+) RNAs as a "self" neutralization phase to suppress innate sensing pathways in an RNA structure-dependent manner, proposing potential therapeutic targets for virus-infectious diseases.