PARP11X2 establishes a PARylation–ubiquitin signaling checkpoint that suppresses teleost interferon immunity

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Post-translational ADP-ribosylation is increasingly recognized as a critical regulator of antiviral signaling, yet its roles in lower vertebrate immunity remain poorly understood. Here, we show that diverse aquatic DNA and RNA viruses dynamically remodel host ADP-ribosylation, revealing this modification as a important immunoregulatory layer during fish virus infection. Pharmacological inhibition of PARP activity can restrict viral replication and potentiate interferon-mediated antiviral responses, highlighting ADP-ribosylation as a targetable host pathway. Focusing on orange-spotted grouper nervous necrosis virus (OGNNV), we identify PARP11 X2 as an infection-induced negative regulator of antiviral immunity. Mechanistically, PARP11X2 selectively suppresses IFNd-dependent, but not IFNh-dependent, JAK–STAT signaling by promoting degradation of the IFNd receptor CRFB5. Unlike mammalian PARP11-mediated regulation, PARP11X2 catalyzes poly-ADP-ribosylation of the E3 ligase β-TrCP, which promotes K27-linked ubiquitination of CRFB5, contributing to its proteasomal turnover, uncovering a previously unrecognized coupling between PARylation and noncanonical ubiquitin signaling in antiviral receptor control. This signaling axis dampens interferon-stimulated gene induction and facilitates NNV replication. Importantly, clinically approved PARP inhibitors, particularly Olaparib, disrupt this suppressive pathway, restore IFNd antiviral activity, and inhibit viral infection. Together, our findings reveal an evolutionarily diverged PARylation–ubiquitination checkpoint that selectively controls IFNd receptor stability in teleost fish, uncovering species-specific principles of interferon regulation that are absent from mammalian systems.

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