Updated project metadata. Epstein-Barr virus (EBV) causes infectious mononucleosis, triggers multiple sclerosis and is associated with 200,000 cancers/year. EBV colonizes the B-cell compartment and periodically reactivates, inducing expression of 80 viral proteins. Yet much remains unknown about how EBV remodels host cells and dismantles key antiviral responses. We therefore created a proteomic map of EBV-host and EBV-EBV interactions in B-cells undergoing EBV replication, uncovering conserved herpesvirus versus EBV-specific host cell targets. The EBV-encoded G-protein coupled receptor BILF1 associated with MAVS and the UFM1 E3 ligase UFL1. Whereas UFMylation of 14-3-3 proteins drives RIG-I/MAVS signaling, BILF1-directed MAVS UFMylation instead triggered MAVS packaging into mitochondrial-derived vesicles and lysosomal proteolysis. In the absence of BILF1, EBV replication activated the NLRP3 inflammasome, which impaired viral replication and triggered pyroptosis. Our results provide a viral protein interaction network resource, reveal a UFM1-dependent pathway for selective degradation of mitochondrial cargo and highlight BILF1 as a novel therapeutic target.