The African swine fever virus MGF300-4L protein is associated with viral pathogenicity by promoting the autophagic degradation of IKKβ and increasing the stability of IκBα

文献类型： 外文期刊

第一作者： Wang, Tao

作者： Wang, Tao;Luo, Rui;Zhang, Jing;Lan, Jing;Lu, Zhanhao;Zhai, Huanjie;Li, Lian-Feng;Sun, Yuan;Qiu, Hua-Ji;Lan, Jing;Qiu, Hua-Ji

作者机构：

关键词： African swine fever virus; MGF300-4L; IKK beta; I kappa B alpha; chaperone-mediated autophagy

期刊名称：EMERGING MICROBES & INFECTIONS （ 影响因子：13.2； 五年影响因子：9.9 ）

ISSN：

年卷期： 2024 年 13 卷 1 期

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收录情况： SCI

摘要： African swine fever (ASF) is a highly contagious, often fatal viral disease caused by African swine fever virus (ASFV), which imposes a substantial economic burden on the global pig industry. When screening for the virus replication-regulating genes in the left variable region of the ASFV genome, we observed a notable reduction in ASFV replication following the deletion of the MGF300-4L gene. However, the role of MGF300-4L in ASFV infection remains unexplored. In this study, we found that MGF300-4L could effectively inhibit the production of proinflammatory cytokines IL-1 beta and TNF-alpha, which are regulated by the NF-kappa B signaling pathway. Mechanistically, we demonstrated that MGF300-4L interacts with IKK beta and promotes its lysosomal degradation via the chaperone-mediated autophagy. Meanwhile, the interaction between MGF300-4L and I kappa B alpha competitively inhibits the binding of the E3 ligase beta-TrCP to I kappa B alpha, thereby inhibiting the ubiquitination-dependent degradation of I kappa B alpha. Remarkably, although ASFV encodes other inhibitors of NF-kappa B, the MGF300-4L gene-deleted ASFV (Del4L) showed reduced virulence in pigs, indicating that MGF300-4L plays a critical role in ASFV pathogenicity. Importantly, the attenuation of Del4L was associated with a significant increase in the production of IL-1 beta and TNF-alpha early in the infection of pigs. Our findings provide insights into the functions of MGF300-4L in ASFV pathogenicity, suggesting that MGF300-4L could be a promising target for developing novel strategies and live attenuated vaccines against ASF.

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