Structure-based Prediction Reveals FAM105A as an African Swine Fever Virus I215L Interactor

African swine fever virus (ASFV) causes a fatal hemorrhagic disease in pigs, leading to severe economic losses worldwide. The viral ubiquitin-conjugating enzyme I215L (E2) is critical for ASFV replication and modulation of host antiviral responses. Host deubiquitinating enzymes (DUBs) bind to E2 enzymes to inhibit the transfer of ubiquitin. In this study, we systematically screened 34 swine DUBs using HDOCK docking and AlphaFold3 modeling, identifying FAM105A as the most probable interactor. Co-immunoprecipitation assay validated the interaction between I215L and FAM105A. Structural analyses revealed seven I215L residues (E19, N20, M99, S102, A104, D108, S116) that form defined polar contacts, among which M99, D108, and S116 are critical for binding stability. These findings identify FAM105A as a novel host target of ASFV I215L, establishing a new paradigm for studying viral-host protein interactions.