Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322, USA.
Arizona State University, Center for Immunotherapy, Vaccines and Virotherapy, Biodesign Institute, Tempe, AZ 85287, USA.
Cell Host Microbe. 2021 Aug 11;29(8):1266-1276.e5. doi: 10.1016/j.chom.2021.05.009. Epub 2021 Jun 29.
Necroptosis mediated by Z-nucleic-acid-binding protein (ZBP)1 (also called DAI or DLM1) contributes to innate host defense against viruses by triggering cell death to eliminate infected cells. During infection, vaccinia virus (VACV) protein E3 prevents death signaling by competing for Z-form RNA through an N-terminal Zα domain. In the absence of this E3 domain, Z-form RNA accumulates during the early phase of VACV infection, triggering ZBP1 to recruit receptor interacting protein kinase (RIPK)3 and execute necroptosis. The C-terminal E3 double-strand RNA-binding domain must be retained to observe accumulation of Z-form RNA and induction of necroptosis. Substitutions of Zα from either ZBP1 or the RNA-editing enzyme double-stranded RNA adenosine deaminase (ADAR)1 yields fully functional E3 capable of suppressing virus-induced necroptosis. Overall, our evidence reveals the importance of Z-form RNA generated during VACV infection as a pathogen-associated molecular pattern (PAMP) unleashing ZBP1/RIPK3/MLKL-dependent necroptosis unless suppressed by viral E3.
Z 核酸结合蛋白（ZBP）1（也称为 DAI 或 DLM1）介导的细胞坏死参与了先天宿主对病毒的防御，通过触发细胞死亡来清除受感染的细胞。在感染过程中，牛痘病毒（VACV）蛋白 E3 通过其 N 端 Zα 结构域与 Z 型 RNA 竞争，从而防止死亡信号的传递。在缺乏这种 E3 结构域的情况下，Z 型 RNA 在 VACV 感染的早期阶段积累，触发 ZBP1 招募受体相互作用蛋白激酶（RIPK）3 并执行细胞坏死。必须保留 C 端 E3 双链 RNA 结合域，才能观察到 Z 型 RNA 的积累和细胞坏死的诱导。ZBP1 或 RNA 编辑酶双链 RNA 腺苷脱氨酶（ADAR）1 的 Zα 取代产生完全功能的 E3，能够抑制病毒诱导的细胞坏死。总的来说，我们的证据表明，VACV 感染过程中产生的 Z 型 RNA 作为一种病原体相关分子模式（PAMP）释放 ZBP1/RIPK3/MLKL 依赖性细胞坏死，除非被病毒 E3 抑制。
