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

文献类型： 外文期刊

第一作者： Wu, Pan-Xue

作者： Wu, Pan-Xue;Du, Xu-Guang;Zhao, Yao-Feng;Wu, Sen;Wu, Pan-Xue;Yang, Wen-Ping;Feng, Tao;Zhang, Jing;Zhu, Guo-Qiang;Ru, Yi;Li, Dan;Zheng, Hai-Xue;Yang, Wen-Ping;Feng, Tao;Zhang, Jing;Ru, Yi;Li, Dan

作者机构：

关键词： African swine fever virus; I177L; inflammatory response; TRAF6; TAK1; NLRP3 inflammasome

期刊名称：JOURNAL OF VIROLOGY （ 影响因子：3.8； 五年影响因子：3.9 ）

ISSN： 0022-538X

年卷期： 2025 年 99 卷 4 期

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收录情况： SCI

摘要： 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-kappa B 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-1 beta. TAK1 inhibition efficiently reverses ASFV-activated NF-kappa B 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.

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