JMJD6-Mediated Epigenetic Silencing of Innate Immunity Promotes Pseudorabies Virus Replication

Jumonji domain-containing protein 6 (JMJD6) has been implicated in epigenetic regulation. Here, we demonstrated that JMJD6 was upregulated during pseudorabies virus (PRV) infection and critically enhanced viral replication by promoting virion release. Mechanistically, JMJD6 suppressed PRV-induced histone H4K16 acetylation, a modification associated with chromatin relaxation and DNA damage response activation. This epigenetic modulation attenuated the cGAS–STING-mediated innate immune signaling pathway, leading to reduced interferon production and enhanced viral propagation. Furthermore, we identified METTL23 as a nuclear interactor of JMJD6 upon viral infection, revealing a cooperative role between these proteins in facilitating immune evasion. Importantly, administration of the JMJD6-specific inhibitor JMJD6-IN-1 potently activated innate immunity and restricted PRV replication in mice. Our findings unveil a novel epigenetic strategy employed by PRV to evade host antiviral responses and highlight JMJD6 as a potential therapeutic target for combating herpesvirus infections.