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Inhibition of DAI-dependent necroptosis by the Z-DNA binding domain of the vaccinia virus innate immune evasion protein, E3.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2017 Oct 24; Vol. 114 (43), pp. 11506-11511. Date of Electronic Publication: 2017 Oct 09. - Publication Year :
- 2017
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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 virus-induced necroptosis. VACV deleted of the Zα domain of E3 (VACV-E3LΔ83N) 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. VACV-E3LΔ83N 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.<br />Competing Interests: The authors declare no conflict of interest.
- Subjects :
- Animals
Caspases metabolism
Cell Death
Cell Line
Cell Survival
DNA, Z-Form chemistry
Glycoproteins genetics
Humans
Immunity, Innate
Interferon Type I chemistry
Interferon Type I pharmacology
Mice
Protein Domains
RNA-Binding Proteins chemistry
Receptor-Interacting Protein Serine-Threonine Kinases genetics
Receptor-Interacting Protein Serine-Threonine Kinases metabolism
Vaccinia virus immunology
Vaccinia virus pathogenicity
Viral Proteins chemistry
Virulence
DNA, Z-Form metabolism
Glycoproteins metabolism
RNA-Binding Proteins metabolism
Vaccinia virus metabolism
Viral Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 114
- Issue :
- 43
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 29073079
- Full Text :
- https://doi.org/10.1073/pnas.1700999114