Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322, USA.
Cell Host Microbe. 2012 Mar 15;11(3):290-7. doi: 10.1016/j.chom.2012.01.016.
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 with RIP3(-/-) mice, vIRA mutant MCMV pathogenesis is restored in DAI(-/-) 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.
程序性细胞坏死与细胞凋亡类似，也是宿主防御的一个组成部分，可以清除被病原体感染的细胞。受体相互作用蛋白激酶（RIP）3（也称为 RIPK3）介导了由鼠巨细胞病毒（MCMV）感染或死亡受体激活诱导的、依赖于 RIP 同源相互作用基序（RHIM）的程序性细胞坏死，这种坏死受到 MCMV 编码的 RIP 激活抑制剂（vIRA）的抑制。我们发现干扰素非依赖性表达 DNA 依赖性干扰素调节因子激活物（DAI，也称为 ZBP1 或 DLM-1）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，DAI(-/-) 小鼠中 vIRA 突变型 MCMV 的发病机制得到了恢复，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性凋亡。这些研究揭示了 DAI 作为 RIP3 伴侣介导病毒诱导的坏死的作用。
