Fig. 4

Schematic representation of m⁶A modification in DNA virus infection. A The EBV latent antigen EBNA3C upregulates the level of the methyltransferase METTL14. EBNA3C cooperates with METTL14 to promote cell growth and proliferation. BZLF1 repressed METTL3 expression by binding to the promoter. However, low expression of METTL3 repress the host gene KLF4. Conversely, high expression of KLF4 promotes BZLF1 expression and lytic infection of EBV in epithelial cells. METTL3 promotes the production of progeny virions and expression of the late viral lytic protein BKRF4, BALF4 in Akata cells. Furthermore, METTL3 enhances EBNA2 expression. YTHDF1 promotes the binding of RNA degradation complexes (ZAP, DDX17, and DCP2) to the mRNAs of BZLF1 and BRLF1 to suppress EBV infection and replication. B The m⁶A demethylase FTO decreases the levels of m⁶A and enhances TPA induction of KSHV lytic gene expression. m⁶A nuclear reader protein YTHDC1 and the related splicing factors SRSF3 and SRSF10 bind to several m⁶A sites on the RTA (a key KSHV lytic switch protein) pre-mRNA, which are essential for its splicing. In the cytoplasm, YTHDF2 mediates degradation of KSHV transcripts, leading to repression of viral replication