BioFrontiers Institute, Department of Molecular, Cellular, and Developmental Biology, University of Colorado Boulder, Boulder, CO 80303, USA.
Department of Molecular Biosciences, LaMontagne Center for Infectious Disease, University of Texas at Austin, Austin, TX 78712, USA.
Cell Host Microbe. 2017 Nov 8;22(5):627-638.e7. doi: 10.1016/j.chom.2017.10.003. Epub 2017 Nov 5.
TRIM25 is an E3 ubiquitin ligase that activates RIG-I to promote the antiviral interferon response. The NS1 protein from all strains of influenza A virus binds TRIM25, although not all virus strains block the interferon response, suggesting alternative mechanisms for TRIM25 action. Here we present a nuclear role for TRIM25 in specifically restricting influenza A virus replication. TRIM25 inhibits viral RNA synthesis through a direct mechanism that is independent of its ubiquitin ligase activity and the interferon pathway. This activity can be inhibited by the viral NS1 protein. TRIM25 inhibition of viral RNA synthesis results from its binding to viral ribonucleoproteins (vRNPs), the structures containing individual viral RNA segments, the viral polymerase, and multiple viral nucleoproteins. TRIM25 binding does not inhibit initiation of capped-RNA-primed viral mRNA synthesis by the viral polymerase. Rather, the onset of RNA chain elongation is inhibited because TRIM25 prohibits the movement of RNA into the polymerase complex.
TRIM25 是一种 E3 泛素连接酶，可激活 RIG-I 促进抗病毒干扰素反应。所有流感 A 病毒株的 NS1 蛋白都与 TRIM25 结合，尽管并非所有病毒株都能阻断干扰素反应，这表明 TRIM25 具有替代作用机制。在这里，我们提出了 TRIM25 在特异性限制流感 A 病毒复制中的核作用。TRIM25 通过一种直接机制抑制病毒 RNA 合成，该机制独立于其泛素连接酶活性和干扰素途径。这种活性可以被病毒 NS1 蛋白抑制。TRIM25 抑制病毒 RNA 合成是由于其与病毒核糖核蛋白（vRNP）结合，vRNP 是包含单个病毒 RNA 片段的结构、病毒聚合酶和多种病毒核蛋白。TRIM25 结合不会抑制病毒聚合酶起始帽 RNA 启动的病毒 mRNA 合成。相反，由于 TRIM25 阻止 RNA 进入聚合酶复合物，RNA 链延伸的开始受到抑制。
