Duck plague virus LORF2 utilizes RNF34 to inhibit antiviral innate immunity by ubiquitination and degradation of IRF7.

Abstract

Duck plague, caused by the alphaherpesvirus Duck plague virus (DPV), is an acute, hemorrhagic, and economically devastating disease of waterfowl. DPV infection induces severe immunosuppression, yet the mechanisms by which this pathogen subverts host innate immunity, particularly through manipulation of the host ubiquitin system, remain unclear. The cGAS-STING signaling pathway is a cornerstone of anti-DNA viral immunity. In avian species, where IRF3 has been evolutionarily lost, the transcription factor IRF7 plays a pivotal role in activating type I interferons (IFN-I). Here, we identify duck RNF34 (DuRNF34) as a host E3 ubiquitin ligase that broadly suppresses the duck cGAS-STING pathway by targeting multiple components, including DucGAS, DuSTING, and DuIRF7, for ubiquitination and degradation. Importantly, DPV infection upregulates DuRNF34 expression, which selectively targets DuIRF7 for degradation to facilitate viral replication. Further affinity purification-mass spectrometry (AP-MS) analysis revealed that LORF2, a DPV-specific protein, recruits DuRNF34 to catalyze K11- and K48-linked polyubiquitination of DuIRF7 at lysine residues K51 and K453, leading to DuIRF7 degradation and suppression of IFN-β and downstream antiviral genes. Functional validation confirmed that siRNA-mediated knockdown of LORF2 markedly attenuated DPV-induced DuIRF7 degradation and impaired viral replication. Collectively, these findings reveal a novel immune evasion strategy in which DPV hijacks the host E3 ligase DuRNF34 via its unique protein LORF2, thereby targeting DuIRF7 for degradation to subvert innate immunity. This work provides new insights into herpesviral immune evasion and suggests potential targets for therapeutic intervention.