北京
近日，中国农业科学院赵东明、盛相鹏、步志高团队在Nature Communications（IF=15.7）在线发表其最新研究成果，该研究首次阐明宿主因子亲环蛋白 A（CypA/PPIA）对 ASFV 复制的关键调控作用，证实宿主蛋白 CypA 是 p72 的特异性互作蛋白；CypA 可在体内外与 p72 结合，并通过疏水空腔识别 p72 暴露区域。
非洲猪瘟（ASF）是当前危害全球养猪业最为严重的烈性传染病，已造成巨大经济损失。该病以家猪和野猪高发病率、高死亡率为特征，被世界动物卫生组织（WOAH）列为法定报告动物疫病。目前尚无安全有效的商品化疫苗与抗病毒药物，非洲猪瘟防控形势极为严峻。
非洲猪瘟病毒（ASFV）为非洲猪瘟的病原，是一类结构复杂的大型双链 DNA 病毒，病毒粒子呈二十面体对称。ASFV 粒子直径约 200 nm，具有多层结构，依次包含核样体（含病毒基因组）、核心壳、内囊膜、二十面体衣壳及外层脂质囊膜。主要衣壳蛋白 p72 是 ASFV 粒子中丰度最高的结构蛋白，约占病毒总量的 1/3，是衣壳组装的核心组分。目前，p72 蛋白的稳定性调控机制尚不明确。
免疫共沉淀（co-IP）结合质谱分析明确 CypA 与 p72 存在特异性相互作用，并通过 AlphaFold3 结构模拟、定点突变及结合实验进一步验证了该互作的分子基础。机制上，CypA 与 p72 结合可保护 p72 不被 K63 位泛素化介导的蛋白酶体降解；抑制或敲低 CypA 则显著加速 p72 降解，进而抑制病毒复制。在 ASFV 感染过程中，抑制 CypA 可通过降低 p72 蛋白积累，破坏病毒工厂形成并阻碍病毒粒子组装。
Figure. Proposed model of CypA -mediated regulation of ASFV p72 stability and viral replication
总之，本研究首次证实宿主亲环蛋白 A（CypA）是调控 p72 稳定性及 ASFV 感染的关键宿主因子，揭示了宿主介导的 ASFV 衣壳蛋白稳定性调控新机制，明确 CypA 可作为抗 ASFV 药物研发的重要潜在靶点，为非洲猪瘟防控提供了新的理论依据与策略方向。
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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