Summary
The methylation of RNA at the N6 position of adenosine (m6A) orchestrates multiple biological processes to control development, differentiation, and cell cycle, as well as various aspects of the virus life cycle. How the m6A RNA modification pathway is regulated to finely tune these processes remains poorly understood. Here, we discovered the m6A reader YTHDF2 as a caspase substrate via proteome-wide prediction, followed by in vitro and in vivo experimental 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 m6A modification of CASP8 mRNA and YTHDF2 cleavage during EBV replication. Further, we discovered that caspases cleave multiple components within the m6A RNA modification pathway to benefit EBV replication. Together, our study establishes caspase disarming the m6A RNA modification machinery in fostering EBV reactivation.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
↵8 Lead Contact
Highlights
Proteome-wide scanning identifies the m6A reader YTHDF2 as a caspase substrate
YTHDF2 is cleaved by caspases at two conserved sites to promote EBV replication
YTHDF2 targets CASP8 mRNA to control caspase-8 activation and viral replication
Caspases cleave multiple m6A writers and readers to foster EBV replication
In Brief Zhang et al. discover that multiple components of the m6A modification pathway are cleaved by caspases to foster the replication of a common tumor virus EBV. They show a feedback regulation between YTHDF2 and caspase-8 via m6A modification of CASP8 mRNA as well as caspase-mediated cleavage of YTHDF2 in controlling viral reactivation.