The African swine fever virus I10L protein inhibits the NF-κB signaling pathway by targeting IKKβ

文献类型： 外文期刊

第一作者： Chen, Xing

作者： Chen, Xing;Yang, Zhong-Yuan;Fan, Shuai;Shi, Lan-Fang;Ren, Zi-Yu;Cao, Xue-Jing;Zhang, Yuhang;Han, Shichong;Wan, Bo;Zhang, Gaiping;He, Wen-Rui;Li, Lian-Feng;Li, Meilin;Qiu, Hua-Ji;Zhang, Yuhang;Han, Shichong;Wan, Bo;He, Wen-Rui;Zhang, Gaiping

作者机构：

关键词： African swine fever virus; inflammatory response; I10L protein; IKK beta

期刊名称：JOURNAL OF VIROLOGY （ 影响因子：5.4； 五年影响因子：4.9 ）

ISSN： 0022-538X

年卷期： 2023 年 97 卷 9 期

页码：

收录情况： SCI

摘要： Proinflammatory factors play important roles in the pathogenesis of African swine fever virus (ASFV), which is the causative agent of African swine fever (ASF), a highly contagious and severe hemorrhagic disease. Efforts in the prevention and treatment of ASF have been severely hindered by knowledge gaps in viral proteins responsible for modulating host antiviral responses. In this study, we identified the I10L protein (pI10L) of ASFV as a potential inhibitor of the TNF-alpha- and IL-1 beta-triggered NF-kappa B signaling pathway, the most canonical and important part of host inflammatory responses. The ectopically expressed pI10L remarkably suppressed the activation of NF-kappa B signaling in HEK293T and PK-15 cells. The ASFV mutant lacking the I10L gene (ASFV(Delta I10L)) induced higher levels of proinflammatory cytokines production in primary porcine alveolar macrophages (PAMs) compared with its parental ASFV HLJ/2018 strain (ASFV(WT)). Mechanistic studies suggest that pI10L inhibits IKK beta phosphorylation by reducing the K63-linked ubiquitination of NEMO, which is necessary for the activation of IKK beta. Morever, pI10L interacts with the kinase domain of IKK beta through its N-terminus, and consequently blocks the association of IKK beta with its substrates I kappa B alpha and p65, leading to reduced phosphorylation. In addition, the nuclear translocation efficiency of p65 was also altered by pI10L. Further biochemical evidence supported that the amino acids 1-102 on pI10L were essential for the pI10L-mediated suppression of the NF-kappa B signaling pathway. The present study clarifies the immunosuppressive activity of pI10L, and provides novel insights into the understanding of ASFV pathobiology and the development of vaccines against ASF. IMPORTANCE African swine fever (ASF), caused by the African swine fever virus (ASFV), is now widespread in many countries and severely affects the commercial rearing of swine. To date, few safe and effective vaccines or antiviral strategies have been marketed due to large gaps in knowledge regarding ASFV pathobiology and immune evasion mechanisms. In this study, we deciphered the important role of the ASFV-encoded I10L protein in the TNF-alpha-/IL-1 beta-triggered NF-kappa B signaling pathway. This study provides novel insights into the pathogenesis of ASFV and thus contributes to the development of vaccines against ASF.

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