Abstract
African swine fever virus (ASFV) is a large DNA virus that poses a major threat to the global swine industry. Its virion is encapsulated by an icosahedral capsid predominantly composed of the structural protein p72, which constitutes approximately one-third of the total virion mass. Despite its abundance, the mechanisms regulating p72 stability remain poorly understood. Here, we demonstrate that host-mediated stabilization of p72 is essential for efficient ASFV replication. Mass spectrometry of p72 co-precipitates identified host cyclophilin A (CypA, also known as PPIA) as a key binding partner of p72. CypA interacts with p72 both in vitro and in vivo, specifically engaging exposed regions of p72 via its hydrophobic cavity. CypA interaction stabilizes p72 by reducing its ubiquitination and preventing proteasomal degradation, whereas cyclic CypA inhibitors destabilize p72 by disrupting this interaction and promoting its ubiquitination. Importantly, genetic or pharmacological inhibition of CypA markedly impairs ASFV replication. Mechanistically, CypA inhibition disrupts viral factory formation and virion assembly by decreasing p72 protein accumulation without affecting its transcription. Together, our findings uncover a host-dependent mechanism regulating capsid protein stability and highlight host CypA as a promising target for antiviral strategies against ASFV.
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Data availability
The mass spectrometry data generated in this study have been deposited in the ProteomeXchange Consortium via the iProX partner repository under accession code PXD073232. The RNA-seq data generated in this study have been deposited in the Gene Expression Omnibus (GEO) under accession code GSE300823. The previously published PDB structures referred to in this study include 3K0N, 1CWA, 1CWM, and 5HSV. All data are available within the Article, Supplementary Information, or Source Data file. Source data are provided with this paper.
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Acknowledgements
We thank Dr. Geng Meng (China Agricultural University) for providing the properly folded recombinant p72 trimer protein. We are also grateful to Dr. Qingrun Li (Shanghai Advanced Research Institute, Chinese Academy of Sciences) for assistance with mass spectrometry analysis. This work was supported by the National Key Research and Development Program of China (2021YFD1800101, 2022YFD1800604 to D.Z.), the Central Public-interest Scientific Institution Basal Research Fund (CAAS-ZDRW202409 to D.Z., 1610302024005 and Y2026YC65 to X.S.), the Innovation Program of the Chinese Academy of Agricultural Sciences (CAAS-CSLPDCP-202301 to D.Z.), and the Heilongjiang Provincial Natural Science Foundation of China (JQ2023C005 to D.Z.).
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D.Z. and X.S. conceived and supervised the project. H.K. and L.Y. performed the majority of the experiments, with assistance from Z.Z., Y.Zhang, and L.L. L.Y. and L.S. provided support with bioinformatics analyses. W.W., Y.Zhu, E.S., F.L., and Z.B. contributed essential materials and methodology. D.Z., X.S., H.K., and L.Y. analyzed and organized the data. X.S. prepared the figures and wrote the manuscript. D.Z., X.S., and H.K. revised and edited the manuscript. All authors reviewed and approved the final version of the manuscript.
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Kong, H., Yang, L., Zhang, Z. et al. Cyclophilin A stabilizes the capsid protein p72 to facilitate African swine fever virus replication. Nat Commun (2026). https://doi.org/10.1038/s41467-026-70430-2
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DOI: https://doi.org/10.1038/s41467-026-70430-2
