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.

由 Z-核酸结合蛋白 (ZBP)1（也称为 DAI 或 DLM1）介导的坏死性凋亡通过触发细胞死亡以消除受感染的细胞，有助于宿主对病毒的先天防御。在感染期间，痘苗病毒 (VACV) 蛋白 E3 通过 N 端 Zα 结构域竞争 Z 型 RNA 来防止死亡信号传导。在没有这个 E3 结构域的情况下，Z 型 RNA 在 VACV 感染的早期积累，触发 ZBP1 募集受体相互作用蛋白激酶 (RIPK)3 并执行坏死性凋亡。必须保留 C 端 E3 双链 RNA 结合结构域以观察 Z 型 RNA 的积累和坏死性凋亡的诱导。用 ZBP1 或 RNA 编辑酶双链 RNA 腺苷脱氨酶 (ADAR)1 替换 Zα，可产生功能齐全的 E3，能够抑制病毒诱导的坏死性凋亡。全面的，