Song Jie, Li Jiangnan, Li Shuai, Zhao Gaihong, Li Tingting, Chen Xin, Hu Boli, Liu Jia, Lai Xinyu, Liu Sitong, Zhou Qiongqiong, Huang Li, Weng Changjiang
Division of Fundamental Immunology, National African Swine Fever Para-reference Laboratory, State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, Heilongjiang, China.
Heilongjiang Provincial Key Laboratory of Veterinary Immunology, Harbin, China.
J Virol. 2025 Jan 31;99(1):e0170124. doi: 10.1128/jvi.01701-24. Epub 2024 Dec 17.
During viral infections, autophagy functions as a cell-intrinsic defense mechanism by facilitating the delivery of virions or viral components to the endosomal/lysosomal pathway for degradation. In this study, we report that internalized African swine fever virus (ASFV) virions enter autolysosomes during the early phase of viral infection. Autophagy selectively targets the major capsid protein p72 within the ASFV virion. The ASFV p72 protein undergoes modification through ubiquitination at the C-terminus, a process mediated by the E3 ubiquitin ligase Stub1. Subsequently, ubiquitinated p72 is recognized by the autophagy receptor SQSTM1/p62 through its ubiquitin-binding domain. Stub1 facilitates the ubiquitination and degradation of p72 in an HSPA8-dependent manner selective autophagy. Autophagy plays a critical role in disassembling ASFV virions and further promotes the release of ASFV genomic DNA. These findings support the notion that autophagy is involved in and contributes to the capsid disassembly of ASFV, providing valuable insights into this essential viral process.IMPORTANCEAfrican swine fever (ASF), a highly contagious disease caused by the ASF virus (ASFV), affects domestic pigs and wild boars, with a mortality rate of up to 100%. The ASF epidemic poses a persistent threat to the global pig industry. Currently, no effective vaccines or antiviral drugs are available for prevention and control. In this study, we discovered that autophagy promotes the degradation of p72 and the disassembly of the capsid during the early phase of ASFV infection. Mechanically, Stub1 facilitates the polyubiquitination of ASFV p72 through the chaperone HSPA8. The polyubiquitinated p72 then interacts with the autophagy receptor SQSTM1/p62, leading to its degradation the selective autophagy pathway. These findings reveal the mechanism of p72 degradation through autophagy and provide new insights into the capsid disassembly process of ASFV.
在病毒感染期间，自噬通过促进病毒粒子或病毒成分传递至内体/溶酶体途径进行降解，从而发挥细胞内在防御机制的作用。在本研究中，我们报告内化的非洲猪瘟病毒（ASFV）粒子在病毒感染早期进入自噬溶酶体。自噬选择性地靶向ASFV病毒粒子内的主要衣壳蛋白p72。ASFV p72蛋白在C末端通过泛素化进行修饰，这一过程由E3泛素连接酶Stub1介导。随后，泛素化的p72通过其泛素结合结构域被自噬受体SQSTM1/p62识别。Stub1以依赖HSPA8的方式促进p72的泛素化和降解——选择性自噬。自噬在拆解ASFV病毒粒子过程中起关键作用，并进一步促进ASFV基因组DNA的释放。这些发现支持了自噬参与并有助于ASFV衣壳拆解的观点，为这一重要的病毒过程提供了有价值的见解。
重要性
非洲猪瘟（ASF）是由非洲猪瘟病毒（ASFV）引起的一种高度传染性疾病，影响家猪和野猪，死亡率高达100%。ASF疫情对全球养猪业构成持续威胁。目前，尚无有效的疫苗或抗病毒药物用于预防和控制。在本研究中，我们发现自噬在ASFV感染早期促进p72的降解和衣壳的拆解。机制上，Stub1通过伴侣蛋白HSPA8促进ASFV p72的多聚泛素化。多聚泛素化的p72随后与自噬受体SQSTM1/p62相互作用，导致其通过选择性自噬途径降解。这些发现揭示了通过自噬降解p72的机制，并为ASFV衣壳拆解过程提供了新的见解。
