The S273R protein of African swine fever virus antagonizes the canonical NF-κB signaling pathway by IκBα.

IF 4 2区 医学 Q2 VIROLOGY
Haojie Ren, Lan-Fang Shi, Yanjin Wang, Xiao-Ya Pan, Su Li, Yu-He Ma, Jun-Hao Fan, Xing Chen, Zhong-Yuan Yang, Shuai Fan, Yuhang Zhang, Shichong Han, Wen-Rui He, Bo Wan, Hua-Ji Qiu, Gai-Ping Zhang
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Abstract

African swine fever virus (ASFV) is a large double-stranded DNA virus, which is the causative agent of African swine fever (ASF), a devastating disease of suids epidemic in many countries. The virus has developed multiple strategies to evade surveillance from the host immune system. Inflammatory responses, especially the NF-κB signaling pathway, play central roles in ASFV pathogenesis and immunoevasion. In this study, we identified the ASFV S273R protein (pS273R) as an antagonist of the canonical NF-κB signaling pathway independently of its protease activity. The ectopically expressed pS273R markedly inhibited the tumor necrosis factor-alpha or interleukin-1 beta-triggered NF-κB signaling pathway in HEK293T and PK-15 cells. Silencing pS273R by RNA interference led to elevated expression levels of proinflammatory cytokines in the ASFV-infected primary porcine alveolar macrophages. Mechanistically, pS273R functioned independently of its protease activity. pS273R was associated with the NF-κB complex and interrupted the translocation of IκBα into the proteasome, resulting in the increased stability of IκBα and subsequently impaired nuclear translocation of p65. Furthermore, the core domain (amino acids 83-273) of pS273R was essential for the pS273R-mediated inhibition of the NF-κB signaling pathway. These findings demonstrate the immunosuppressive role of pS273R and provide novel insights into ASFV biological characteristics.IMPORTANCEAfrican swine fever (ASF) is a hemorrhagic disease of suids caused by African swine fever virus (ASFV), with morbidity and mortality rates of up to 100%. The disease has led to significant economic losses to the global swine industry. In this study, we identify the ASFV S273R protein (pS273R) as an antagonist of the canonical NF-κB signaling pathway. Our findings demonstrate the immunosuppressive role of pS273R, which will contribute to a better understanding of the pathogenesis of ASFV and may contribute to the development of antiviral therapies against ASF.

非洲猪瘟病毒S273R蛋白通过i -κB α拮抗典型NF-κB信号通路。
非洲猪瘟病毒(African swine fever virus, ASFV)是一种大型双链DNA病毒,是非洲猪瘟(African swine fever, ASF)的病原体。这种病毒已经发展出多种策略来逃避宿主免疫系统的监视。炎症反应,特别是NF-κB信号通路,在ASFV发病和免疫逃避中起核心作用。在这项研究中,我们发现ASFV S273R蛋白(pS273R)是一种独立于蛋白酶活性的典型NF-κB信号通路的拮抗剂。异位表达的pS273R显著抑制HEK293T和PK-15细胞中肿瘤坏死因子- α或白细胞介素-1 β触发的NF-κB信号通路。通过RNA干扰沉默pS273R导致asfv感染的原代猪肺泡巨噬细胞中促炎细胞因子的表达水平升高。在机制上,pS273R独立于蛋白酶活性发挥作用。pS273R与NF-κB复合物相关,阻断了i -κB α向蛋白酶体的易位,导致i -κB α的稳定性增加,随后损害了p65的核易位。此外,pS273R的核心结构域(氨基酸83-273)对于pS273R介导的NF-κB信号通路的抑制至关重要。这些发现证明了pS273R的免疫抑制作用,并为ASFV生物学特性提供了新的见解。非洲猪瘟(ASF)是由非洲猪瘟病毒(ASFV)引起的猪的出血性疾病,发病率和死亡率高达100%。这种疾病给全球养猪业造成了重大的经济损失。在这项研究中,我们发现ASFV S273R蛋白(pS273R)是典型NF-κB信号通路的拮抗剂。我们的研究结果证实了pS273R的免疫抑制作用,这将有助于更好地了解ASFV的发病机制,并可能有助于开发针对ASF的抗病毒治疗方法。
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来源期刊
Journal of Virology
Journal of Virology 医学-病毒学
CiteScore
10.10
自引率
7.40%
发文量
906
审稿时长
1 months
期刊介绍: Journal of Virology (JVI) explores the nature of the viruses of animals, archaea, bacteria, fungi, plants, and protozoa. We welcome papers on virion structure and assembly, viral genome replication and regulation of gene expression, genetic diversity and evolution, virus-cell interactions, cellular responses to infection, transformation and oncogenesis, gene delivery, viral pathogenesis and immunity, and vaccines and antiviral agents.
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