DPV UL38 stabilizes MFN2 to subvert MAVS-mediated antiviral immunity in ducks.

Duck plague is a highly contagious disease caused by duck plague virus (DPV) infection, leading to high morbidity (up to 100 %) and mortality rates (up to 95 %) among ducks. Mitochondria are essential organelles for virus replication. It is crucial to deepen the understanding of mitochondrial homeostasis and the interaction between mitochondrial proteins after viral infection. However, the interaction between DPV and mitochondria is currently under-researched. In this study, it was first discovered that DPV infection promotes mitochondrial fusion. Subsequently, we tested the role of duck mitochondria fusion protein 2 (MFN2) in DPV infection in duck embryo fibroblast (DEF) cells. Our data demonstrated that DPV infection increases the protein level of MFN2 and inhibits the interferon (IFN) signaling pathway, while exogenous or knockdown expression of MFN2 promotes or curbs DPV replication, respectively. Moreover, MFN2 interacts with mitochondrial antiviral signaling protein (MAVS), promoting its degradation and thereby inhibiting IFN signaling. In addition, MFN2 interacts with DPV proteins UL38, which increases the stability of MFN2 and accumulates reactive oxygen species (ROS) level and inhibits RIG-I-like receptors (RLRs) mediated antiviral responses. Mechanism study demonstrated that multiple interaction regions are present between UL38 and MFN2 to protect MFN2 against CCCP induced degradation via inhibiting ubiquitination on MFN2. Our findings provide a theoretical basis for understanding the pathogenic mechanism of DPV infection, identifying potential antiviral targets, and may also serve as a reference for other herpesviruses' studies.