近日，中國農(nóng)業(yè)科學(xué)院趙東明、盛相鵬、步志高團隊在Nature Communications（IF=15.7）在線發(fā)表其最新研究成果，該研究首次闡明宿主因子親環(huán)蛋白 A（CypA/PPIA）對 ASFV 復(fù)制的關(guān)鍵調(diào)控作用，證實宿主蛋白 CypA 是 p72 的特異性互作蛋白；CypA 可在體內(nèi)外與 p72 結(jié)合，并通過疏水空腔識別 p72 暴露區(qū)域。

非洲豬瘟（ASF）是當(dāng)前危害全球養(yǎng)豬業(yè)最為嚴重的烈性傳染病，已造成巨大經(jīng)濟損失。該病以家豬和野豬高發(fā)病率、高死亡率為特征，被世界動物衛(wèi)生組織（WOAH）列為法定報告動物疫病。目前尚無安全有效的商品化疫苗與抗病毒藥物，非洲豬瘟防控形勢極為嚴峻。

非洲豬瘟病毒（ASFV）為非洲豬瘟的病原，是一類結(jié)構(gòu)復(fù)雜的大型雙鏈 DNA 病毒，病毒粒子呈二十面體對稱。ASFV 粒子直徑約 200 nm，具有多層結(jié)構(gòu)，依次包含核樣體（含病毒基因組）、核心殼、內(nèi)囊膜、二十面體衣殼及外層脂質(zhì)囊膜。主要衣殼蛋白 p72 是 ASFV 粒子中豐度最高的結(jié)構(gòu)蛋白，約占病毒總量的 1/3，是衣殼組裝的核心組分。目前，p72 蛋白的穩(wěn)定性調(diào)控機制尚不明確。

免疫共沉淀（co-IP）結(jié)合質(zhì)譜分析明確 CypA 與 p72 存在特異性相互作用，并通過 AlphaFold3 結(jié)構(gòu)模擬、定點突變及結(jié)合實驗進一步驗證了該互作的分子基礎(chǔ)。機制上，CypA 與 p72 結(jié)合可保護 p72 不被 K63 位泛素化介導(dǎo)的蛋白酶體降解；抑制或敲低 CypA 則顯著加速 p72 降解，進而抑制病毒復(fù)制。在 ASFV 感染過程中，抑制 CypA 可通過降低 p72 蛋白積累，破壞病毒工廠形成并阻礙病毒粒子組裝。

Figure. Proposed model of CypA -mediated regulation of ASFV p72 stability and viral replication

總之，本研究首次證實宿主親環(huán)蛋白 A（CypA）是調(diào)控 p72 穩(wěn)定性及 ASFV 感染的關(guān)鍵宿主因子，揭示了宿主介導(dǎo)的 ASFV 衣殼蛋白穩(wěn)定性調(diào)控新機制，明確 CypA 可作為抗 ASFV 藥物研發(fā)的重要潛在靶點，為非洲豬瘟防控提供了新的理論依據(jù)與策略方向。

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.