结节性皮肤病病毒ORF142通过nbr1介导的STING自噬降解抑制cGAS/STING介导的IFN-I通路

IF 3.5 3区 医学 Q3 IMMUNOLOGY
Microbial pathogenesis Pub Date : 2025-11-01 Epub Date: 2025-08-05 DOI:10.1016/j.micpath.2025.107959
Jingyu Wang, Zhen Wang, Shaobing Wan, Shaotang Ye, Qi Li, Yongbo Liu, Xing Liu, Zihan Chen, Shizhe Liu, Qingmei Xie, Heng Wang, Kun Jia, Shoujun Li
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引用次数: 0

摘要

瘤状皮肤病(LSD)是由瘤状皮肤病病毒(LSDV)引起的,对全球养牛业构成重大威胁。病毒蛋白进化出了逃避宿主免疫反应的能力。在这里,我们证明LSDV感染可以抑制Madin-Darby牛肾(MDBK)细胞中干扰素-β (IFN-β)的产生,即使在仙台病毒(SEV)诱导剂存在的情况下也是如此。通过进一步的研究,我们在LSDV基因组的两端发现了多个强烈抑制IFN-β或NF-κB启动子激活的基因。值得注意的是,ORF142选择性抑制IFN-β启动子活性,但不能抑制NF-κB启动子活性。随后,我们发现ORF142负向调节cGAS/ sting介导的IFN-I的产生。ORF142过表达可抑制IFN-β和干扰素刺激反应元件(ISRE)活性,而ORF142缺失可上调MDBK细胞中IFN-β和干扰素刺激基因(ISGs)的转录水平。从机制上讲,ORF142与STING相互作用,通过募集NBR1促进自噬溶酶体降解,从而阻碍下游信号分子(如IRF3)的激活,抑制IFN-I的产生。总之,我们的研究结果阐明了LSDV编码的ORF142的免疫逃避机制,为开发抗病毒药物或减轻LSD的减毒活疫苗提供了见解。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Lumpy skin disease virus ORF142 suppresses the cGAS/STING-mediated IFN-I pathway through NBR1-mediated STING autophagic degradation.

Lumpy skin disease (LSD), caused by the Lumpy skin disease virus (LSDV), poses a significant threat to the global cattle farming industry. Viral proteins evolved the ability to escape host immune responses. Here, we demonstrate that LSDV infection inhibits interferon-β (IFN-β) production in Madin-Darby bovine kidney (MDBK) cells, even in the presence of Sendai virus (SEV) inducers. Through further investigation, we identify multiple genes at both ends of the LSDV genome that strongly inhibit IFN-β or NF-κB activation of the promoter. Notably, ORF142 selectively inhibits IFN-β promoter activity but fails to inhibit NF-κB promoter activity. Subsequently, we reveal that ORF142 negatively regulate the cGAS/STING-mediated IFN-I production. Overexpression of ORF142 suppresses IFN-β and interferon-stimulated response element (ISRE) activity, while the absence of ORF142 upregulates the transcription levels of IFN-β and interferon-stimulated genes (ISGs) in MDBK cells. Mechanistically, ORF142 interacts with STING to facilitate autophagy-lysosomal degradation by recruiting NBR1, thereby impeding the activation of downstream signaling molecules, such as IRF3, and inhibiting IFN-I production. In conclusion, our findings elucidate the immune evasion mechanism of ORF142 encoded by LSDV, offering insights for the development of antiviral drugs or attenuated live vaccines to mitigate LSD.

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来源期刊
Microbial pathogenesis
Microbial pathogenesis 医学-免疫学
CiteScore
7.40
自引率
2.60%
发文量
472
审稿时长
56 days
期刊介绍: Microbial Pathogenesis publishes original contributions and reviews about the molecular and cellular mechanisms of infectious diseases. It covers microbiology, host-pathogen interaction and immunology related to infectious agents, including bacteria, fungi, viruses and protozoa. It also accepts papers in the field of clinical microbiology, with the exception of case reports. Research Areas Include: -Pathogenesis -Virulence factors -Host susceptibility or resistance -Immune mechanisms -Identification, cloning and sequencing of relevant genes -Genetic studies -Viruses, prokaryotic organisms and protozoa -Microbiota -Systems biology related to infectious diseases -Targets for vaccine design (pre-clinical studies)
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