Cell Host & Microbe
Volume 29, Issue 8, 11 August 2021, Pages 1266-1276.e5
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Article
Vaccinia virus E3 prevents sensing of Z-RNA to block ZBP1-dependent necroptosis

https://doi.org/10.1016/j.chom.2021.05.009Get rights and content
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Highlights

  • Vaccinia virus infection results in production of cytoplasmic Z-RNA

  • Zα domains of vaccinia E3 and host ZBP1 compete for Z-RNA

  • ZBP1 senses Z-RNA and drives necroptosis unless prevented by vaccinia E3 Zα

  • E3 complexed with dsRNA promotes Z-RNA formation

Summary

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.

Keywords

cell death
poxvirus
DAI
ZBP1
Z-form nucleic acid
Z-DNA-binding domain
E3L
Z-RNA
VACV
necroptosis

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