African swine fever virus I10L protein inhibits autolysosome formation by disrupting RAB7-HOPS complex-dependent SNARE complex assembly

  • Autophagy. 2026 May 15:1-16. doi: 10.1080/15548627.2026.2672727.
Meng Chen  1  2 ,  Yongjie Sunkang  3  4 ,  Tong Cheng  5 ,  Lei Liu  6  7 ,  Huanan Li  1  2 ,  Huajin Yuan  1  2 ,  Lihong Huang  3  4 ,  Lei Sun  8  9 ,  Wenbao Qi  3  4 ,  Yingli Shang  1  2
Affiliations
  • 1. Department of Preventive Veterinary Medicine, College of Veterinary Medicine, Shandong Agricultural University, Taian, Shandong, China.
  • 2. Shandong Provincial Key Laboratory of Zoonoses, Shandong Agricultural University, Taian, Shandong, China.
  • 3. Key Laboratory for Zoonosis, Ministry of Agriculture and Rural Affairs, Guangzhou, China.
  • 4. Guangdong Laboratory for Lingnan Modern Agriculture, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China.
  • 5. CAS Key Laboratory of Molecular Virology and Immunology, Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, Shanghai, China.
  • 6. State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
  • 7. Beijing Institute for Stem Cell and Regenerative Medicine, University of Chinese Academy of Sciences, Beijing, China.
  • 8. CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
  • 9. School of Medicine, University of Chinese Academy of Sciences, Beijing, China.
PMID: 42138513 DOI: 10.1080/15548627.2026.2672727
Abstract

Macroautophagy/Autophagy serves as a crucial cellular defense mechanism against invading pathogens. However, viruses have evolved diverse strategies to evade or even exploit Autophagy for their own replication. In this study, we reveal that the African swine fever virus (ASFV)-encoded I10L protein suppresses Autophagy by blocking autophagosome-lysosome fusion. Mechanistically, I10L directly interacts with the endolysosomal RAB GTPase RAB7, a master regulator of vesicle docking at late endosomes and lysosomes. This interaction competitively prevents RAB7 from binding to VPS39, a core component of the homotypic fusion and vacuole protein sorting (HOPS) complex. Consequently, I10L disrupts the assembly of the STX17-SNAP29-VAMP8 SNARE complex, which is essential for autophagosome-lysosome fusion. ASFV Infection thus induces autophagosome accumulation, whereas I10L deletion reverses this effect and attenuates viral replication in primary macrophages. Our findings uncover a novel immune evasion strategy by which ASFV subverts lysosomal degradation through RAB7-HOPS axis manipulation, providing both mechanistic insights into viral pathogenicity and potential therapeutic targets for Antiviral development.Abbreviations: ASFV: African swine fever virus; GEF: guanine nucleotide exchange factor; GFP: green fluorescent protein; HOPS: homotypic fusion and vacuole protein sorting; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; PAMs: primary alveolar macrophages; RAB7: RAB7, member Ras oncogene family; siRNA: small interfering RNA; SNAP29: synaptosome associated protein 29; SNARE: soluble N-ethylmaleimide-sensitive factor attachment protein receptor; SQSTM1/p62: sequestosome 1; STX17: syntaxin 17; TM: transmembrane domain; VAMP8: vesicle associated membrane protein 8; VPS39: VPS39 subunit of HOPS complex; VPS41: VPS41 subunit of HOPS complex; YKT6: YKT6 vesicular SNARE protein.

Keywords
ASFV; HOPS complex; I10L; Ras-related protein 7; SNARE complex; autophagosome-lysosome fusion.
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