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

  • Cell Rep. 2025 Nov 19;44(12):116594. doi: 10.1016/j.celrep.2025.116594.
Keke Wu  1 ,  Bingke Li  2 ,  Ruibo Zhao  2 ,  Ye Bai  2 ,  Sen Zeng  2 ,  Hongxing Ding  2 ,  Lin Yi  2 ,  Shuangqi Fan  3 ,  Jinding Chen  4
Affiliations
  • 1. College of Veterinary Medicine, South China Agricultural University, Guangzhou, China; Key Laboratory of Animal Vaccine Development, Ministry of Agriculture and Rural Affairs, Guangzhou, China; Key Laboratory of Zoonosis Prevention and Control of Guangdong Province, South China Agricultural University, Guangzhou, China; College of Veterinary Medicine, South China Agricultural University, 483 Wushan Road, Tianhe District, Guangzhou, Guangdong, China.
  • 2. College of Veterinary Medicine, South China Agricultural University, Guangzhou, China; Key Laboratory of Animal Vaccine Development, Ministry of Agriculture and Rural Affairs, Guangzhou, China; Key Laboratory of Zoonosis Prevention and Control of Guangdong Province, South China Agricultural University, Guangzhou, China.
  • 3. College of Veterinary Medicine, South China Agricultural University, Guangzhou, China; Key Laboratory of Animal Vaccine Development, Ministry of Agriculture and Rural Affairs, Guangzhou, China; Key Laboratory of Zoonosis Prevention and Control of Guangdong Province, South China Agricultural University, Guangzhou, China; College of Veterinary Medicine, South China Agricultural University, 483 Wushan Road, Tianhe District, Guangzhou, Guangdong, China. Electronic address: [email protected].
  • 4. College of Veterinary Medicine, South China Agricultural University, Guangzhou, China; Key Laboratory of Animal Vaccine Development, Ministry of Agriculture and Rural Affairs, Guangzhou, China; Key Laboratory of Zoonosis Prevention and Control of Guangdong Province, South China Agricultural University, Guangzhou, China; College of Veterinary Medicine, South China Agricultural University, 483 Wushan Road, Tianhe District, Guangzhou, Guangdong, China. Electronic address: [email protected].
PMID: 41269859 DOI: 10.1016/j.celrep.2025.116594
Abstract

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.

Keywords
COPS2-SNAP29 axis; CP: microbiology; SNARE; antiviral target; autolysosomal exocytosis; autophagic flux hijacking; enveloped RNA viruses; non-lytic viral egress; ubiquitination.
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