COPS2 coordinates biphasic autophagy hijacking for non-lytic propagation of enveloped RNA viruses

Autophagy serves as a cellular defense against pathogens, while viruses exploit it through evolutionary arms races. Here, using Classical Swine Fever Virus (CSFV), an enveloped RNA pestivirus threatening global swine industries, we uncover a biphasic autophagy-hijacking strategy coordinated by COP9 signalosome subunit 2 (COPS2). Mechanistically, CSFV hijacks COPS2-mediated K11/K48-linked ubiquitination of viral P7 protein to create an autophagy recognition signal and facilitate virus entry into autophagosomes. In addition, COPS2 drives STX17-SNAP29-VAMP8 complex assembly by inhibiting SNAP29 O-GlcNAcylation, accelerating autophagosome-lysosome fusion to generate exocytosis-competent autolysosomes for viral release. This spatiotemporal regulation enables non-lytic viral propagation via autolysosomal exocytosis. Our study provides the first evidence that RNA viruses commandeer both ends of the autophagy machinery for complete replication cycles, identifying COPS2 as a master coordinator of autophagic flux hijacking and revealing the COPS2-SNAP29 axis as a conserved therapeutic target against enveloped RNA viruses.