Inhibition of DAI-dependent necroptosis by the Z-DNA binding domain of the vaccinia virus innate immune evasion protein, E3

Heather Koehler, Samantha Cotsmire, Jeffrey Langland, Karen Kibler, Daniel Kalman, Jason W. Upton, Edward S. Mocarski, Bertram Jacobs

Research output: Contribution to journalArticle

27 Scopus citations

Abstract

Vaccinia virus (VACV) encodes an innate immune evasion protein, E3, which contains an N-terminal Z-nucleic acid binding (Zα) domain that is critical for pathogenicity in mice. Here we demonstrate that the N terminus of E3 is necessary to inhibit an IFN-primed virusinduced necroptosis. VACV deleted of the Zα domain of E3 (VACVE3Lδ83N) induced rapid RIPK3-dependent cell death in IFN-treated L929 cells. Cell death was inhibited by the RIPK3 inhibitor, GSK872, and infection with this mutant virus led to phosphorylation and aggregation of MLKL, the executioner of necroptosis. In 293T cells, induction of necroptosis depended on expression of RIPK3 as well as the host-encoded Zα domain-containing DNA sensor, DAI. VACVE3Lδ83N is attenuated in vivo, and pathogenicity was restored in either RIPK3- or DAI-deficient mice. These data demonstrate that the N terminus of the VACV E3 protein prevents DAI-mediated induction of necroptosis.

Original languageEnglish (US)
Pages (from-to)11506-11511
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number43
DOIs
StatePublished - Oct 24 2017

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Keywords

  • Necroptosis
  • RIPK3
  • Type 1 interferon
  • Vaccinia
  • Z-DNA binding domain

ASJC Scopus subject areas

  • General

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