Pseudorabies virus hijacks JNK to reprogram m⁶A machinery for sustaining replication

Area of Science:

• Virology
• Molecular Biology
• Immunology

Background:

• Pseudorabies virus (PRV) alters host inflammatory responses and RNA epitranscriptomics.
• The precise mechanisms connecting these processes during PRV infection are not fully understood.

Purpose of the Study:

• To elucidate the regulatory circuit coordinating PRV replication and host inflammatory responses.
• To investigate the role of RNA methylation (m⁶A) in PRV pathogenesis.

Main Methods:

• Methylated RNA immunoprecipitation sequencing (MeRIP-seq) to map m⁶A modification sites.
• Biochemical analyses to assess protein interactions and enzymatic activity.
• In vitro and in vivo experiments to evaluate antiviral strategies.

Main Results:

• PRV infection activates JNK, leading to WTAP phosphorylation, nuclear export, and reduced m⁶A on host transcripts, especially inflammatory cytokines.
• Global m⁶A hypomethylation stabilizes host inflammatory cytokine mRNAs (TNF-α, IL-1β, IL-18) and viral transcripts, promoting PRV replication.
• Inhibition of JNK or restoration of m⁶A suppressed PRV replication.
• m⁶A hypomethylation stabilized DUSP5 transcripts, creating a negative feedback loop by transiently restraining JNK.

Conclusions:

• PRV reprograms the host m⁶A epitranscriptome via a JNK-WTAP-m⁶A-DUSP5 regulatory circuit.
• Targeting RNA methylation machinery presents a promising antiviral strategy against PRV.