Yang Jinke, Yang Bo, Hao Yu, Shi Xijuan, Yang Xing, Zhang Dajun, Zhao Dengshuai, Yan Wenqian, Chen Lingling, Bie Xintian, Chen Guohui, Zhu Zixiang, Li Dan, Shen Chaochao, Li Guoli, Liu Xiangtao, Zheng Haixue, Zhang Keshan
State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou 730000, China.
State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou 730000, China.
Virus Res. 2023 Oct 15;336:199198. doi: 10.1016/j.virusres.2023.199198. Epub 2023 Sep 11.
African swine fever virus (ASFV) infection causes African swine fever (ASF), a virulent infectious disease that threatens the safety of livestock worldwide. Studies have shown that MGF360-9 L is important for the virulence of ASFV and the host protein HS1-associated protein X-1 (HAX1) plays an important role in viral pathogenesis. This study aimed to clarify the mechanism by which HAX1 mediates ASFV replication through interactions with MGF360-9 L. The regions of interaction between MGF360-9 L and HAX1 were predicted and validated. HAX1 overexpression and RNA interference studies revealed that HAX1 is a host restriction factor that suppresses ASFV replication. Moreover, HAX1 expression was inhibited in ASFV-infected mature bone marrow-derived macrophages, and infection with the virulent MGF360-9 L gene deletion strain (∆MGF360-9 L) attenuated the inhibitory effect of the wild-type strain (WT) on HAX1 expression, suggesting a complex regulatory relationship between MGF360-9 L and HAX1. Furthermore, the E3 ubiquitin ligase RNF114 interacted with MGF360-9 L and HAX1, MGF360-9 L degraded HAX1 through the ubiquitin-proteasome pathway, and RNF114 facilitated the degradation of HAX1 by MGF360-9L-linked K48 ubiquitin chains through the ubiquitin-proteasome pathway, thereby facilitating ASFV replication. In conclusion, this study has enriched our understanding of the regulatory networks between ASFV proteins and host proteins and provided a reference for investigation into the pathogenesis and immune escape mechanism of ASFV.
非洲猪瘟病毒（ASFV）感染会引发非洲猪瘟（ASF），这是一种烈性传染病，威胁着全球牲畜的安全。研究表明，MGF360-9L对ASFV的毒力很重要，宿主蛋白HS1相关蛋白X-1（HAX1）在病毒致病过程中发挥重要作用。本研究旨在阐明HAX1通过与MGF360-9L相互作用介导ASFV复制的机制。预测并验证了MGF360-9L与HAX1之间的相互作用区域。HAX1过表达和RNA干扰研究表明，HAX1是一种抑制ASFV复制的宿主限制因子。此外，在ASFV感染的成熟骨髓来源巨噬细胞中HAX1表达受到抑制，而用毒性MGF360-9L基因缺失株（∆MGF360-9L）感染可减弱野生型毒株（WT）对HAX1表达的抑制作用，这表明MGF360-9L与HAX1之间存在复杂的调控关系。此外，E3泛素连接酶RNF114与MGF360-9L和HAX1相互作用，MGF360-9L通过泛素-蛋白酶体途径降解HAX1，RNF114通过泛素-蛋白酶体途径促进MGF360-9L连接的K48泛素链对HAX1的降解，从而促进ASFV复制。总之，本研究丰富了我们对ASFV蛋白与宿主蛋白之间调控网络的理解，并为研究ASFV的致病机制和免疫逃逸机制提供了参考。
