Caspases Switch off the m(6)A RNA Modification Pathway to Foster the Replication of a Ubiquitous Human Tumor Virus

The methylation of RNA at the N6 position of adenosine (m(6)A) orchestrates multiple biological processes to control development, differentiation, and cell cycle, as well as various aspects of the virus life cycle. How the m(6)A RNA modification pathway is regulated to finely tune these processes remains poorly understood. Here, we discovered the m(6)A reader YTHDF2 as a caspase substrate via proteome-wide prediction, followed by in vitro and in vivo validations. We further demonstrated that cleavage-resistant YTHDF2 blocks, while cleavage-mimicking YTHDF2 fragments promote, the replication of a common human oncogenic virus, Epstein-Barr virus (EBV). Intriguingly, our study revealed a feedback regulation between YTHDF2 and caspase-8 via m(6)A modification of CASP8 mRNA and YTHDF2 cleavage during EBV replication. Further, we discovered that caspases cleave multiple components within the m(6)A RNA modification pathway to benefit EBV replication. Our study establishes that caspase disarming of the m(6)A RNA modification machinery fosters EBV replication.