The MGF300-2R protein of African swine fever virus is associated with viral pathogenicity by promoting the autophagic degradation of IKKα and IKKβ through the recruitment of TOLLIP.

IF 6.7 1区 医学 Q1 Immunology and Microbiology
PLoS Pathogens Pub Date : 2023-08-11 eCollection Date: 2023-08-01 DOI:10.1371/journal.ppat.1011580
Tao Wang, Rui Luo, Jing Zhang, Zhanhao Lu, Lian-Feng Li, Yong-Hui Zheng, Li Pan, Jing Lan, Huanjie Zhai, Shujian Huang, Yuan Sun, Hua-Ji Qiu
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引用次数: 1

Abstract

The multigene family genes (MGFs) in the left variable region (LVR) of the African swine fever virus (ASFV) genome have been reported to be involved in viral replication in primary porcine alveolar macrophages (PAMs) and virulence in pigs. However, the exact functions of key MGFs in the LVR that regulate the replication and virulence of ASFV remain unclear. In this study, we identified the MGF300-2R gene to be critical for viral replication in PAMs by deleting different sets of MGFs in the LVR from the highly virulent strain ASFV HLJ/18 (ASFV-WT). The ASFV mutant lacking the MGF300-2R gene (Del2R) showed a 1-log reduction in viral titer, and induced higher IL-1β and TNF-α production in PAMs than did ASFV-WT. Mechanistically, the MGF300-2R protein was found to interact with and degrade IKKα and IKKβ via the selective autophagy pathway. Furthermore, we showed that MGF300-2R promoted the K27-linked polyubiquitination of IKKα and IKKβ, which subsequently served as a recognition signal for the cargo receptor TOLLIP-mediated selective autophagic degradation. Importantly, Del2R exhibited a significant reduction in both replication and virulence compared with ASFV-WT in pigs, likely due to the increased IL-1β and TNF-α, indicating that MGF300-2R is a virulence determinant. These findings reveal that MGF300-2R suppresses host innate immune responses by mediating the degradation of IKKα and IKKβ, which provides clues to paving the way for the rational design of live attenuated vaccines to control ASF.

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非洲猪瘟病毒的MGF300-2R蛋白通过募集TOLLIP促进IKKα和IKKβ的自噬降解,与病毒致病性有关。
据报道,非洲猪瘟病毒(ASFV)基因组左可变区(LVR)中的多基因家族基因(MGFs)参与了原代猪肺泡巨噬细胞(PAM)中的病毒复制和猪的毒力。然而,调节ASFV复制和毒力的LVR中关键MGF的确切功能尚不清楚。在本研究中,我们通过从高毒力菌株ASFV HLJ/18(ASFV-WT)的LVR中删除不同组的MGF,鉴定了MGF300-2R基因对病毒在PAM中复制至关重要。与ASFV-WT相比,缺乏MGF300-2R基因(Del2R)的ASFV突变体的病毒滴度降低了1个对数,并在PAM中诱导了更高的IL-1β和TNF-α产生。从机制上讲,MGF300-2R蛋白通过选择性自噬途径与IKKα和IKKβ相互作用并降解。此外,我们发现MGF300-2R促进IKKα和IKKβ的K27连接的多泛素化,这随后作为货物受体TOLLIP介导的选择性自噬降解的识别信号。重要的是,与猪ASFV-WT相比,Del2R在复制和毒力方面均显著降低,这可能是由于IL-1β和TNF-α增加,表明MGF300-2R是毒力决定因素。这些发现表明,MGF300-2R通过介导IKKα和IKKβ的降解来抑制宿主先天免疫反应,这为合理设计控制ASF的减毒活疫苗提供了线索。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
PLoS Pathogens
PLoS Pathogens 生物-病毒学
CiteScore
11.40
自引率
3.00%
发文量
598
审稿时长
2 months
期刊介绍: Bacteria, fungi, parasites, prions and viruses cause a plethora of diseases that have important medical, agricultural, and economic consequences. Moreover, the study of microbes continues to provide novel insights into such fundamental processes as the molecular basis of cellular and organismal function.
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