African swine fever virus I177L induces host inflammatory responses by facilitating the TRAF6-TAK1 axis and NLRP3 inflammasome assembly.

IF 4 2区 医学 Q2 VIROLOGY
Pan-Xue Wu, Wen-Ping Yang, Tao Feng, Jing Zhang, Guo-Qiang Zhu, Xu-Guang Du, Yi Ru, Yao-Feng Zhao, Sen Wu, Dan Li, Hai-Xue Zheng
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引用次数: 0

Abstract

African swine fever virus (ASFV) is the pathogen of African swine fever (ASF), and its infection causes a lethal disease in pigs, with severe pathological lesions. These changes indicate excessive inflammatory responses in infected pigs, which is the main cause of death, but the ASFV proteins worked in this physiological process and the mechanisms underlying ASFV-induced inflammation remain unclear. Here, we identify that viral I177L works in these inflammatory responses. Mechanistically, I177L facilitates TRAF6 ubiquitination that enhances its binding to TAK1, which promotes TAK1 ubiquitination and phosphorylation. These processes depend on the E3 ubiquitin ligase activity of TRAF6. The upregulation of I177L to TRAF6-TAK1 interaction and TAK1 activation is responsible for I177L's activated effect on the NF-κB signaling pathway. Additionally, I177L promotes assembly of the NLRP3 inflammasome and ASC oligomerization, thus leading to the activation of the NLRP3 inflammasome and the production and secretion of mature IL-1β. TAK1 inhibition efficiently reverses ASFV-activated NF-κB signaling and inflammatory responses and suppresses ASFV replication. Furthermore, I177L-deficient ASFV induces milder inflammatory responses in pigs compared with parental ASFV, which still protects pigs against ASFV challenge. The finding confirms ASFV I177L as an important proinflammatory protein in vitro and in vivo and reveals a key mechanism underlying ASFV-mediated inflammatory responses for the first time, which enriches our knowledge of the complex ASFV, thus benefiting our understanding of the interplay between ASFV infection and the host's inflammatory responses.IMPORTANCEAfrican swine fever (ASF) is a devastating viral disease in pigs, and excessive inflammatory responses induced by ASFV mainly cause death. Thus, the study of the proinflammatory virulent proteins and the detailed mechanisms are important to ASF control. Here, I177L was demonstrated to be an essential protein in ASFV-mediated inflammation, which performs by simultaneously activating the NF-κB signaling and the NLRP3 inflammasome. The finding elucidates the molecular mechanism underlying ASFV-activated inflammatory responses for the first time. It provides a theoretical foundation for reducing the high mortality caused by excessive inflammation and opens new avenues for small-molecule drug development and vaccine design targeting ASFV.

非洲猪瘟病毒I177L通过促进TRAF6-TAK1轴和NLRP3炎性体组装诱导宿主炎症反应。
非洲猪瘟病毒(African swine fever virus, ASFV)是非洲猪瘟(African swine fever, ASF)的病原体,其感染可引起猪的致命疾病,具有严重的病理病变。这些变化表明感染猪的过度炎症反应,这是导致死亡的主要原因,但ASFV蛋白在这一生理过程中起作用,ASFV诱导炎症的机制尚不清楚。在这里,我们发现病毒I177L在这些炎症反应中起作用。在机制上,I177L促进TRAF6泛素化,增强其与TAK1的结合,从而促进TAK1泛素化和磷酸化。这些过程依赖于TRAF6的E3泛素连接酶活性。I177L对TRAF6-TAK1相互作用和TAK1激活的上调是I177L对NF-κB信号通路的激活作用的原因。此外,I177L促进NLRP3炎性小体的组装和ASC寡聚化,从而导致NLRP3炎性小体的激活和成熟IL-1β的产生和分泌。TAK1抑制有效逆转ASFV激活的NF-κB信号和炎症反应,抑制ASFV复制。此外,与亲代ASFV相比,缺乏i177l的ASFV在猪体内诱导的炎症反应较轻,这仍然可以保护猪免受ASFV的攻击。这一发现在体外和体内证实了ASFV I177L是一种重要的促炎蛋白,并首次揭示了ASFV介导的炎症反应的关键机制,丰富了我们对ASFV复合物的认识,从而有助于我们理解ASFV感染与宿主炎症反应之间的相互作用。非洲猪瘟(african swine fever, ASF)是猪的一种毁灭性病毒性疾病,由ASFV引起的过度炎症反应是导致猪死亡的主要原因。因此,研究促炎毒力蛋白及其具体机制对非洲猪瘟的控制具有重要意义。在这里,I177L被证明是asfv介导的炎症的必需蛋白,它通过同时激活NF-κB信号和NLRP3炎症小体来实现。这一发现首次阐明了asfv激活炎症反应的分子机制。这为降低过度炎症引起的高死亡率提供了理论基础,并为针对ASFV的小分子药物开发和疫苗设计开辟了新的途径。
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
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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