Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, USA.
FEBS J. 2020 Oct;287(20):4362-4369. doi: 10.1111/febs.15242. Epub 2020 Feb 24.
Z-nucleic acid binding protein (ZBP)1 (also known as DAI and DLM1) is a pathogen sensor activated by double-strand character RNA to recruit receptor-interacting protein (RIP) kinase via a RIP homotypic interaction motif. The activation of receptor-interacting protein kinase (RIPK)3 and initiation of virus-induced necroptosis were initially reported in a landmark publication Upton et al. (Cell Host Microbe 11: 290, 2012) employing the DNA virus murine cytomegalovirus (MCMV). M45-encoded viral inhibitor of RIP activation prevents virus-induced necroptosis. Additional virus-encoded suppressors of necroptosis were then identified, including herpes simplex virus ICP6 and vaccinia virus E3L. Caspase-8 suppressors encoded by these DNA viruses block apoptosis, unleashing necroptosis mediated through Z-nucleic acid binding protein 1 (ZBP1) recruitment of RIPK3. These studies all utilized ZBP1-deficient mice generated by the Akira Lab (Zbp1 ) to bring the significance of virus-induced necroptosis to light. C57BL/6 mice were chosen as controls based on the assumption that mutant mice were congenic; however, these mice were recently found to display an unexpected innate immune deficit, lacking C57BL/6-specific NK1.1 and Ly49H natural killer cell subpopulations important in the early control of MCMV infection. Short nucleotide polymorphism analysis of Zbp1 breeders revealed a mixed genetic background (~ 71% C57BL/6 DNA and ~ 29% 129). Even though this level of 129 strain background does not alter ZBP1 cell-autonomous function as a sensor and mediator of necroptosis, it confounds innate immune response characteristics. In the future, genetic background must be carefully controlled before implicating ZBP1 function in response characteristics that shape immunity, inflammation, metabolism, and pathogenesis.
Z 核酸结合蛋白 (ZBP)1（也称为 DAI 和 DLM1）是一种病原体传感器，可被双链特征 RNA 激活，通过 RIP 同源相互作用基序募集受体相互作用蛋白激酶 (RIPK)。受体相互作用蛋白激酶 (RIPK)3 的激活和病毒诱导的坏死性凋亡的启动最初是在 Upton 等人的一篇具有里程碑意义的论文中报道的（Cell Host Microbe 11: 290, 2012），该论文使用了 DNA 病毒鼠巨细胞病毒 (MCMV)。M45 编码的病毒 RIP 激活抑制剂可防止病毒诱导的坏死性凋亡。随后又鉴定出其他病毒编码的坏死性凋亡抑制剂，包括单纯疱疹病毒 ICP6 和牛痘病毒 E3L。这些 DNA 病毒编码的半胱天冬酶-8 抑制剂阻断细胞凋亡，释放通过 Z 核酸结合蛋白 1 (ZBP1) 募集 RIPK3 介导的坏死性凋亡。这些研究均利用 Akira 实验室生成的 ZBP1 缺陷小鼠（Zbp1）揭示了病毒诱导的坏死性凋亡的重要性。选择 C57BL/6 小鼠作为对照是基于这样的假设，即突变小鼠是同源的；然而，最近发现这些小鼠表现出意想不到的固有免疫缺陷，缺乏在早期控制 MCMV 感染中起重要作用的 C57BL/6 特异性 NK1.1 和 Ly49H 自然杀伤细胞亚群。Zbp1 饲养者的短核苷酸多态性分析显示出混合的遗传背景（71%的 C57BL/6 DNA 和29%的 129）。尽管这种 129 品系背景水平不会改变 ZBP1 作为坏死性凋亡传感器和介质的细胞自主功能，但它会混淆固有免疫反应特征。在未来，在将 ZBP1 功能与塑造免疫、炎症、代谢和发病机制的反应特征联系起来之前，必须仔细控制遗传背景。
