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Koehler H , Cotsmire S , Zhang T , Balachandran S , Upton JW , Langland J , Kalman D , Jacobs BL , Mocarski ES
Vaccinia virus E3 prevents sensing of Z-RNA to block ZBP1-dependent necroptosis
Cell Host Microbe. 2021 Aug 11;29(8) :1266-1276 e5
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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.
Koehler, Heather Cotsmire, Samantha Zhang, Ting Balachandran, Siddharth Upton, Jason W Langland, Jeffery Kalman, Daniel Jacobs, Bertram L Mocarski, Edward S eng R01 AI095394/AI/NIAID NIH HHS/ Cell Host Microbe. 2021 Aug 11;29(8):1266-1276.e5. doi: 10.1016/j.chom.2021.05.009. Epub 2021 Jun 29.