The African swine fever virus MGF300-4L protein is associated with viral pathogenicity by promoting the autophagic degradation of IKK<i>β</i> and increasing the stability of I<i>κ</i>B<i>α</i>

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 <i>MGF300-4L</i> 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<i>β</i> and TNF-<i>α</i>, which are regulated by the NF-<i>κ</i>B signaling pathway. Mechanistically, we demonstrated that MGF300-4L interacts with IKK<i>β</i> and promotes its lysosomal degradation via the chaperone-mediated autophagy. Meanwhile, the interaction between MGF300-4L and I<i>κ</i>B<i>α</i> competitively inhibits the binding of the E3 ligase <i>β</i>-TrCP to I<i>κ</i>B<i>α</i>, thereby inhibiting the ubiquitination-dependent degradation of I<i>κ</i>B<i>α</i>. Remarkably, although ASFV encodes other inhibitors of NF-<i>κ</i>B, the <i>MGF300-4L</i> 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<i>β</i> and TNF-<i>α</i> 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.

非洲猪瘟（African swine fever, ASF）是由非洲猪瘟病毒（African swine fever virus, ASFV）引发的高传染性、常致死性病毒性疾病，给全球养猪业造成了沉重的经济负担。在筛选非洲猪瘟病毒基因组左侧可变区的病毒复制调控基因时，我们观察到删除&lt;i&gt;MGF300-4L&lt;/i&gt;基因后，非洲猪瘟病毒的复制水平显著降低，但MGF300-4L在非洲猪瘟病毒感染中的作用仍未被阐明。
本研究发现，MGF300-4L可有效抑制由核因子κB（NF-κB）信号通路调控的促炎细胞因子白细胞介素1β（IL-1β）和肿瘤坏死因子α（TNF-α）的产生。机制层面，我们证实MGF300-4L可与IκB激酶β（IKKβ）相互作用，并通过伴侣介导的自噬（chaperone-mediated autophagy）促进其溶酶体降解。同时，MGF300-4L与核因子κB抑制蛋白α（IκBα）的相互作用，可竞争性抑制E3泛素连接酶β-TrCP与IκBα的结合，从而阻断IκBα的泛素依赖性降解。
值得注意的是，尽管非洲猪瘟病毒已编码其他NF-κB信号通路抑制剂，但缺失&lt;i&gt;MGF300-4L&lt;/i&gt;基因的重组病毒（Del4L）在猪体内的毒力有所减弱，表明MGF300-4L在非洲猪瘟病毒的致病过程中发挥关键作用。尤为重要的是，Del4L的减毒特性与猪感染早期IL-1β和TNF-α的分泌量显著升高密切相关。
本研究结果为阐明MGF300-4L在非洲猪瘟病毒致病机制中的功能提供了新视角，提示MGF300-4L可作为开发新型非洲猪瘟防控策略及减毒活疫苗的潜在靶点。

搜集汇总

背景与挑战

背景概述

该数据集聚焦于非洲猪瘟病毒（ASFV）MGF300-4L蛋白的功能研究，揭示了其通过促进IKKβ的自噬降解和增强IκBα稳定性来抑制NF-κB信号通路，从而降低病毒致病性。研究发现MGF300-4L基因缺失会减少病毒复制和促炎细胞因子产生，在猪模型中显示毒力减弱，为开发ASF新型策略和减毒活疫苗提供了潜在靶点。数据集包含相关实验数据文件，适用于医学、微生物学和免疫学等领域的研究。