Pseudorabies virus hijacks JNK to reprogram m6A machinery for sustaining replication

Pseudorabies virus (PRV) reprograms host inflammatory responses and epitranscriptomics, yet how these processes are connected remains unclear. Here, we report a JNK-WTAP-m⁶A-DUSP5 regulatory circuit that coordinates viral replication and inflammatory responses. PRV infection activated c-Jun N-terminal kinase (JNK), which phosphorylated wilms tumor-associated protein (WTAP) to drive its nuclear export and disrupt the activity of the m⁶A methyltransferase complex. Methylated RNA immunoprecipitation sequencing (MeRIP-seq) and biochemical analyses revealed a global reduction of N6-methyladenosine (m⁶A) on host transcripts, particularly on proinflammatory cytokines, alongside widespread m⁶A modification sites on viral transcripts. Consequently, reduced m⁶A prolonged the half-lives of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-18 (IL-18) mRNAs, as well as viral transcripts, thereby synergistically promoting PRV replication. Inhibition of JNK activity or restoration of m⁶A modification suppressed PRV replication in vitro and in vivo . Moreover, the m⁶A hypomethylation stabilized dual-specificity phosphatase 5 (DUSP5) transcripts at early infection, transiently restraining JNK activation and forming a negative feedback loop. These findings demonstrate that PRV reprograms the m⁶A machinery via JNK-mediated WTAP phosphorylation and highlights RNA methylation restoration as a promising antiviral strategy.