Duck plague virus US2 promotes p62-mediated autophagic degradation of RIG-I to suppress antiviral signaling.

Duck plague virus (DPV) is a highly contagious pathogen that causes severe immunosuppression and high mortality in waterfowl, resulting in substantial economic losses to the poultry industry. However, the mechanisms by which DPV evades host innate immune responses remain incompletely understood. In this study, we investigated the role of the DPV tegument protein US2 in regulating host antiviral responses. pUS2 significantly suppressed IFN-β promoter activation induced by poly(I:C) and poly(dA:dT) and reduced the transcription of IFN-β and interferon-stimulated genes (ISGs), including OASL and Mx. Further analysis showed that pUS2 specifically inhibited IFN-β promoter activation triggered by the RIG-I/MDA5-MAVS signaling pathway. Co-immunoprecipitation and immunofluorescence assays demonstrated that pUS2 directly interacted with RIG-I in the cytoplasm and reduced its protein abundance in a dose-dependent manner. Mechanistically, pUS2 enhanced K48-linked ubiquitination of RIG-I and promoted its degradation through a p62-mediated autophagy pathway. Deletion of the US2 gene moderately reduced viral replication efficiency in DEF cells and enhanced expression of type I interferons and ISGs. In vivo experiments further showed that ducks infected with the US2-deleted virus exhibited reduced pathogenicity, including lower viral loads, milder tissue damage, and increased survival rates compared with those infected with the parental virus. Collectively, these findings demonstrate that DPV US2 antagonizes host innate immunity by targeting the RIG-I signaling pathway and promoting RIG-I degradation through autophagy. This study provides new insights into the immune evasion strategies of DPV and advances our understanding of DPV-host interactions.