Direct activation of RIP3/MLKL-dependent necrosis by herpes simplex virus 1 (HSV-1) protein ICP6 triggers host antiviral defense
Direct activation of RIP3/MLKL-dependent necrosis by herpes simplex virus 1 (HSV-1) protein ICP6 triggers host antiviral defense
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单纯疱疹病毒 1 (HSV-1) 蛋白 ICP6 直接激活 RIP3/MLKL 依赖性坏死，触发宿主抗病毒防御
DOI：
10.1073/pnas.1412767111
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发表时间：
2014-10-28
影响因子：
11.1
通讯作者：
He, Sudan
中科院分区：
文献类型：
--
作者：
Wang, Xing;Li, Yun;He, Sudan
意义受体相互作用蛋白3(RIP3)及其底物混合谱系蛋白样蛋白(MLKL)目前被认为是程序性坏死的核心细胞调节因子。程序性坏死被认为参与了宿主对病原体的防御，但对这一主题的机制研究仍然很少。我们发现人类单纯疱疹病毒1型(HSV-1)在宿主细胞中触发RIP3/MLKL依赖的坏死。单纯疱疹病毒1型核糖核苷酸还原酶大亚基(ICP6)是RIP3的直接激活物，足以引发程序性坏死。缺乏RIP3的小鼠表现出对HSV-1复制和致病机制的严重控制。这项研究提供了一个宿主细胞如何利用程序性坏死来启动抗病毒反应的明确案例。受体相互作用蛋白3(RIP3)及其下游底物混合谱系蛋白样蛋白(MLKL)已成为细胞程序性死亡的关键成分。肿瘤坏死因子家族的细胞因子受体和Toll样受体3和4分别通过受体相互作用的激酶-1和Toll/IL-1受体结构域适配子诱导干扰素-β激活RIP3。这种形式的细胞死亡与宿主防御系统有关。然而，除上述受体外，驱动RIP3被多种病原体激活的分子机制在很大程度上尚不清楚。在这里，我们报告了人类单纯疱疹病毒1型(HSV-1)感染触发RIP3依赖的坏死。这一过程需要MLKL，但不依赖于肿瘤坏死因子受体、TLR3、圆柱瘤病和宿主RIP同型相互作用模体包含蛋白DNA依赖的干扰素调节因子激活剂。HSV-1感染后，病毒核糖核苷酸还原酶大亚基(ICP6)与RIP3相互作用。ICP6-RIP3复合体的形成需要这两种蛋白质的Rhim结构域。HSV-1 ICP6缺失突变体未能引起HSV-1感染细胞的有效坏死。此外，异位表达ICP6，而不是Rhim突变体ICP6，可直接激活RIP3/MLKL介导的坏死。缺乏RIP3的小鼠表现出对HSV-1复制和致病机制的严重控制。因此，本研究揭示了一种以前未知的寄主抗病原菌机制。
Significance Receptor-interacting kinase-3 (RIP3) and its substrate mixed lineage kinase domain-like protein (MLKL) are now recognized as the core cellular regulators of programmed necrosis. Programmed necrosis is thought be involved in host defense against pathogens, but the mechanistic studies on the topic are still scarce. We discover that human herpes simplex virus 1 (HSV-1) triggers RIP3/MLKL-dependent necrosis in host cells. HSV-1 ribonucleotide reductase large subunit (ICP6) is found to be a direct activator of RIP3 and sufficient for triggering programmed necrosis. Mice lacking RIP3 exhibited severely impaired control of HSV-1 replication and pathogenesis. This study provides a clear case how host cells use programmed necrosis to mount an antiviral response. The receptor-interacting kinase-3 (RIP3) and its downstream substrate mixed lineage kinase domain-like protein (MLKL) have emerged as the key cellular components in programmed necrotic cell death. Receptors for the cytokines of tumor necrosis factor (TNF) family and Toll-like receptors (TLR) 3 and 4 are able to activate RIP3 through receptor-interacting kinase-1 and Toll/IL-1 receptor domain-containing adapter inducing IFN-β, respectively. This form of cell death has been implicated in the host-defense system. However, the molecular mechanisms that drive the activation of RIP3 by a variety of pathogens, other than the above-mentioned receptors, are largely unknown. Here, we report that human herpes simplex virus 1 (HSV-1) infection triggers RIP3-dependent necrosis. This process requires MLKL but is independent of TNF receptor, TLR3, cylindromatosis, and host RIP homotypic interaction motif-containing protein DNA-dependent activator of IFN regulatory factor. After HSV-1 infection, the viral ribonucleotide reductase large subunit (ICP6) interacts with RIP3. The formation of the ICP6–RIP3 complex requires the RHIM domains of both proteins. An HSV-1 ICP6 deletion mutant failed to cause effective necrosis of HSV-1–infected cells. Furthermore, ectopic expression of ICP6, but not RHIM mutant ICP6, directly activated RIP3/MLKL-mediated necrosis. Mice lacking RIP3 exhibited severely impaired control of HSV-1 replication and pathogenesis. Therefore, this study reveals a previously uncharacterized host antipathogen mechanism.