DAI/ZBP1/DLM-1 Complexes with RIP3 to Mediate Virus-Induced Programmed Necrosis that Is Targeted by Murine Cytomegalovirus vIRA.
DAI/ZBP1/DLM-1 Complexes with RIP3 to Mediate Virus-Induced Programmed Necrosis that Is Targeted by Murine Cytomegalovirus vIRA.
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DOI：
10.1016/j.chom.2019.09.004
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发表时间：
2019-10
影响因子：
30.3
通讯作者：
J. Upton;W. Kaiser;E. Mocarski
中科院分区：
文献类型：
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作者：
J. Upton;W. Kaiser;E. Mocarski
程序性坏死，像细胞凋亡一样，作为宿主防御的一个组成部分，消除了病原体感染的细胞。受体相互作用蛋白激酶（RIP） 3（也称为RIPK3）介导小鼠巨细胞病毒（MCMV）感染或死亡受体激活诱导的RIP同型相互作用基序（RHIM）依赖性程序性坏死，并被MCMV编码的RIP激活病毒抑制剂（vIRA）抑制。我们发现干扰素非依赖性dna依赖性干扰素调节因子激活因子（DAI，也称为ZBP1或DLM-1）的表达使细胞对病毒诱导的坏死敏感，并且DAI敲低或敲除细胞对这种死亡途径具有抗性。重要的是，与rip3−/−小鼠一样，vIRA突变体MCMV的发病机制在dai−/−小鼠中得以恢复，这与DAI-RIP3复合物是vIRA的天然靶标一致。因此，DAI与RIP3相互作用介导病毒诱导的坏死，类似于RIP1-RIP3复合物控制死亡受体诱导的坏死下垂。这些研究揭示了DAI作为RIP3伙伴介导病毒诱导坏死的作用。
Programmed necrosis, like apoptosis, eliminates pathogen-infected cells as a component of host defense. Receptor-interacting protein kinase (RIP) 3 (also called RIPK3) mediates RIP homotypic interaction motif (RHIM)-dependent programmed necrosis induced by murine cytomegalovirus (MCMV) infection or death receptor activation and suppressed by the MCMV-encoded viral inhibitor of RIP activation (vIRA). We find that interferon-independent expression of DNA-dependent activator of interferon regulatory factors (DAI, also known as ZBP1 or DLM-1) sensitizes cells to virus-induced necrosis and that DAI knockdown or knockout cells are resistant to this death pathway. Importantly, as withRIP3−/−mice, vIRA mutant MCMV pathogenesis is restored inDAI−/−mice, consistent with a DAI-RIP3 complex being the natural target of vIRA. Thus, DAI interacts with RIP3 to mediate virus-induced necrosis analogous to the RIP1-RIP3 complex controlling death receptor-induced necroptosis. These studies unveil a role for DAI as the RIP3 partner mediating virus-induced necrosis.