Interferon (IFN) plays a central role in regulating host immune response to viral pathogens through the induction of IFN-Stimulated Genes (ISGs). IFN also enhances cellular SUMOylation and ISGylation, though the functional interplay between these modifications remains unclear. Here, we used a system-level approach to profile global changes in protein abundance in SUMO3-expressing cells stimulated by IFNα. These analyses revealed the stabilization of several ISG factors including SAMHD1, MxB, GBP1, GBP5, Tetherin/BST2 and members of IFITM, IFIT and IFI families. This process was correlated with enhanced IFNα-induced anti-HIV-1 and HSV-1 activities. Also IFNα upregulated protein ISGylation through increased abundance of E2 conjugating enzyme UBE2L6, and E3 ISG15 ligases TRIM25 and HERC5. Remarkably, TRIM25 depletion blocked SUMO3-dependent protein stabilization in response to IFNα. Our data identify a new mechanism by which SUMO3 regulates ISG product stability and reinforces the relevance of the SUMO pathway in controlling both the expression and functions of the restriction factors and IFN antiviral response.

中文翻译：

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响应干扰素的 SUMOylation 和 ISGylation 之间的串扰

干扰素 (IFN) 通过诱导 IFN 刺激基因 (ISG) 在调节宿主对病毒病原体的免疫反应中发挥核心作用。IFN 还增强细胞 SUMOylation 和 ISGylation，尽管这些修饰之间的功能相互作用尚不清楚。在这里，我们使用系统级方法来分析由 IFNα 刺激的 SUMO3 表达细胞中蛋白质丰度的全局变化。这些分析揭示了几个 ISG 因素的稳定性，包括 SAMHD1、MxB、GBP1、GBP5、Tetherin/BST2 以及 IFITM、IFIT 和 IFI 家族的成员。该过程与增强的 IFNα 诱导的抗 HIV-1 和 HSV-1 活性相关。此外，IFNα 通过增加 E2 结合酶 UBE2L6 和 E3 ISG15 连接酶 TRIM25 和 HERC5 的丰度来上调蛋白质 ISGylation。值得注意的是，TRIM25 耗竭阻止 SUMO3 依赖的蛋白质稳定化以响应 IFNα。我们的数据确定了一种新机制，通过该机制 SUMO3 调节 ISG 产品稳定性并加强 SUMO 途径在控制限制因子和 IFN 抗病毒反应的表达和功能方面的相关性。