BVDV antagonizes the antiviral activity of MDA5 by promoting its degradation via CCDC50-dependent selective autophagy

Bovine viral diarrhea-mucosal disease (BVD-MD), caused by bovine viral diarrhea virus (BVDV), is a major infectious disease affecting the cattle industry. The nonstructural protein NS4B of BVDV has been shown to induce autophagy and antagonize the expression of the host innate immune sensor MDA5. However, the precise mechanism underlying NS4B-mediated suppression of MDA5 remains unclear. In this study, we demonstrate that NS4B interacts with the host protein CCDC50, as confirmed by co-immunoprecipitation and indirect immunofluorescence assays. Stable overexpression of CCDC50 significantly promoted MDA5 degradation and enhanced BVDV replication, whereas CCDC50 knockdown markedly impaired NS4B-mediated degradation of MDA5 in HEK293T cells. Interestingly, CCDC50 also suppressed the production of type I interferons (IFN-I) and interferon-stimulated genes (ISGs) during BVDV infection. Furthermore, the translocation of CCDC50 reduced MDA5 protein levels through the autophagy pathway. Mechanistically, we found that CCDC50 interacts with MDA5 and facilitates NS4B-mediated autophagic degradation of MDA5. These findings uncover a novel mechanism by which BVDV NS4B hijacks the host protein CCDC50 to subvert antiviral innate immunity by promoting MDA5 autophagic degradation and suppressing IFN-I signaling.