African swine fever virus (ASFV) is a large DNA virus that is highly contagious and pathogenic in domestic pigs with a mortality rate up to 100%. However, how ASFV suppresses JAK-STAT1 signaling to evade the immune response remains unclear. In this study, we found that the ASFV-encoded protein MGF-505-7R inhibited proinflammatory IFN-γ-mediated JAK-STAT1 signaling. Mechanistically, MGF-505-7R was found to interact with JAK1 and JAK2 and mediate their degradation. Further study indicated that MGF-505-7R promoted degradation of JAK1 and JAK2 by upregulating the E3 ubiquitin ligase RNF125 expression and inhibiting expression of Hes5, respectively. Consistently, MGF-505-7R-deficient ASFV induced high levels of IRF1 expression and displayed compromised replication both in primary porcine alveolar macrophages and pigs compared with wild-type ASFV. Furthermore, MGF-505-7R deficiency attenuated the virulence of the ASFV and pathogenesis of ASF in pigs. These findings suggest that the JAK-STAT1 axis mediates the innate immune response to the ASFV and that MGF-505-7R plays a critical role in the virulence of the ASFV and pathogenesis of ASF by antagonizing this axis. Thus, we conclude that deletion of MGF-505-7R may serve as a strategy to develop attenuated vaccines against the ASFV.

中文翻译：

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非洲猪瘟病毒蛋白 MGF-505-7R 通过抑制 JAK1 和 JAK2 介导的信号传导促进毒力和发病机制。

非洲猪瘟病毒（ASFV）是一种大型DNA病毒，在家猪中具有高度传染性和致病性，死亡率高达100%。然而，ASFV 如何抑制 JAK-STAT1 信号传导以逃避免疫反应仍不清楚。在这项研究中，我们发现 ASFV 编码的蛋白 MGF-505-7R 抑制了促炎性 IFN-γ 介导的 JAK-STAT1 信号传导。从机制上讲，发现 MGF-505-7R 与 JAK1 和 JAK2 相互作用并介导它们的降解。进一步的研究表明，MGF-505-7R 分别通过上调 E3 泛素连接酶 RNF125 的表达和抑制 Hes5 的表达来促进 JAK1 和 JAK2 的降解。与野生型 ASFV 相比，MGF-505-7R 缺陷型 ASFV 在原代猪肺泡巨噬细胞和猪中均诱导高水平的 IRF1 表达并显示复制受损。此外，MGF-505-7R 缺乏减弱了 ASFV 的毒力和 ASF 在猪中的发病机制。这些发现表明 JAK-STAT1 轴介导了对 ASFV 的先天免疫反应，并且 MGF-505-7R 通过拮抗该轴在 ASFV 的毒力和 ASF 的发病机制中起关键作用。因此，我们得出结论，MGF-505-7R 的缺失可作为开发 ASFV 减毒疫苗的策略。