Inhibition of DAI-dependent necroptosis by the Z-DNA binding domain of the vaccinia virus innate immune evasion protein, E3.
Heather KoehlerSamantha CotsmireJeffrey LanglandKaren V KiblerDaniel KalmanJason W UptonEdward S MocarskiBertram L JacobsPublished in: Proceedings of the National Academy of Sciences of the United States of America (2017)
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.
Keyphrases
- innate immune
- cell death
- dna binding
- nucleic acid
- cell cycle arrest
- binding protein
- high glucose
- protein protein
- diabetic rats
- amino acid
- dendritic cells
- induced apoptosis
- transcription factor
- signaling pathway
- machine learning
- type diabetes
- big data
- circulating tumor
- pi k akt
- cystic fibrosis
- adipose tissue
- skeletal muscle
- metabolic syndrome
- pseudomonas aeruginosa
- insulin resistance
- deep learning
- cell proliferation
- artificial intelligence
- sensitive detection