SUMOylation of the m6A reader YTHDF2 by PIAS1 promotes viral RNA decay to restrict EBV replication.

N6-methyladenosine (m6A) RNA modification pathway plays important roles in diverse cellular processes and viral life cycle. Here, we investigated the relationship between PIAS1 and the m6A reader protein YTHDF2, which is involved in regulating RNA stability by binding to m6A-modified RNA. We found that both the N-terminal and C-terminal regions of YTHDF2 interact with PIAS1. We showed that PIAS1 promotes the SUMOylation of YTHDF2 at three specific lysine residues. We also demonstrated that PIAS1 enhances the anti-Epstein-Barr virus (EBV) activity of YTHDF2. We further revealed that PIAS1 mediates the SUMOylation of other YTHDF family members, namely YTHDF1 and YTHDF3, due to their similarities with YTHDF2. These findings together illuminate an important regulatory mechanism of YTHDF2 in controlling viral RNA decay and EBV replication through PIAS1-mediated SUMOylation.