PDF(Pubmed)
Abstract：
YTH N6-methyladenosine RNA-binding protein F2 (YTHDF2) is a member of the YTH protein family that binds to N6-methyladenosine (m6A)-modified RNA, regulating RNA stability and restricting viral replication, including Epstein-Barr virus (EBV). PIAS1 is an E3 small ubiquitin-like modifier (SUMO) ligase known as an EBV restriction factor, but its role in YTHDF2 SUMOylation remains unclear. In this study, we investigated the functional regulation of YTHDF2 by PIAS1. We found that PIAS1 promotes the SUMOylation of YTHDF2 at three specific lysine residues (K281, K571, and K572). Importantly, PIAS1 synergizes with wild-type YTHDF2, but not a SUMOylation-deficient mutant, to limit EBV lytic replication. Mechanistically, YTHDF2 lacking SUMOylation exhibits reduced binding to EBV transcripts, leading to increased viral mRNA stability. Furthermore, PIAS1 mediates SUMOylation of YTHDF2\'s paralogs, YTHDF1 and YTHDF3, to restrict EBV replication. These results collectively uncover a unique mechanism whereby YTHDF family proteins control EBV replication through PIAS1-mediated SUMOylation, highlighting the significance of SUMOylation in regulating viral mRNA stability and EBV replication.IMPORTANCEm6A 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-EBV activity of YTHDF2. We further revealed that PIAS1 mediates the SUMOylation of other YTHDF family members, namely, YTHDF1 and YTHDF3, to limit EBV replication. These findings together illuminate an important regulatory mechanism of YTHDF proteins in controlling viral RNA decay and EBV replication through PIAS1-mediated SUMOylation.
摘要：
目的：m6ARNA修饰通路在多种细胞过程和病毒生命周期中发挥重要作用。这里,我们研究了PIAS1与m6A阅读蛋白YTHDF2之间的关系，该蛋白通过与m6A修饰的RNA结合而参与调节RNA稳定性。我们发现YTHDF2的N端和C端区域都与PIAS1相互作用。我们显示PIAS1促进YTHDF2在三个特定赖氨酸残基处的SUMOylation。我们还证明PIAS1增强YTHDF2的抗EBV活性。我们进一步揭示了PIAS1介导其他YTHDF家族成员的SUMOylation，即,YTHDF1和YTHDF3，以限制EBV的复制。这些发现共同阐明了YTHDF蛋白在通过PIAS1介导的SUMO化控制病毒RNA衰变和EBV复制中的重要调节机制。
