Vaccinia virus E3 prevents sensing of Z-RNA to block ZBP1-dependent necroptosis

Heather Koehler, Samantha Cotsmire, Ting Zhang, Siddharth Balachandran, Jason W. Upton, Jeffery Langland, Daniel Kalman, Bertram L. Jacobs, Edward S. Mocarski

Research output: Contribution to journalArticlepeer-review

54 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1266-1276.e5
JournalCell Host and Microbe
Issue number8
StatePublished - Aug 11 2021


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

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Virology


Dive into the research topics of 'Vaccinia virus E3 prevents sensing of Z-RNA to block ZBP1-dependent necroptosis'. Together they form a unique fingerprint.

Cite this