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Zhang T , Yin C , Boyd DF , Quarato G , Ingram JP , Shubina M , Ragan KB , Ishizuka T , Crawford JC , Tummers B , Rodriguez DA , Xue J , Peri S , Kaiser WJ , Lopez CB , Xu Y , Upton JW , Thomas PG , Green DR , Balachandran S
Influenza Virus Z-RNAs Induce ZBP1-Mediated Necroptosis
Cell. 2020 Mar 19;180(6) :1115-1129.e13
PMID: 32200799    PMCID: PMC7153753    URL: https://www.ncbi.nlm.nih.gov/pubmed/32200799
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Influenza A virus (IAV) is a lytic RNA virus that triggers receptor-interacting serine/threonine-protein kinase 3 (RIPK3)-mediated pathways of apoptosis and mixed lineage kinase domain-like pseudokinase (MLKL)-dependent necroptosis in infected cells. ZBP1 initiates RIPK3-driven cell death by sensing IAV RNA and activating RIPK3. Here, we show that replicating IAV generates Z-RNAs, which activate ZBP1 in the nucleus of infected cells. ZBP1 then initiates RIPK3-mediated MLKL activation in the nucleus, resulting in nuclear envelope disruption, leakage of DNA into the cytosol, and eventual necroptosis. Cell death induced by nuclear MLKL was a potent activator of neutrophils, a cell type known to drive inflammatory pathology in virulent IAV disease. Consequently, MLKL-deficient mice manifest reduced nuclear disruption of lung epithelia, decreased neutrophil recruitment into infected lungs, and increased survival following a lethal dose of IAV. These results implicate Z-RNA as a new pathogen-associated molecular pattern and describe a ZBP1-initiated nucleus-to-plasma membrane "inside-out" death pathway with potentially pathogenic consequences in severe cases of influenza.
1097-4172 Zhang, Ting Yin, Chaoran Boyd, David F Quarato, Giovanni Ingram, Justin P Shubina, Maria Ragan, Katherine B Ishizuka, Takumi Crawford, Jeremy Chase Tummers, Bart Rodriguez, Diego A Xue, Jia Peri, Suraj Kaiser, William J Lopez, Carolina B Xu, Yan Upton, Jason W Thomas, Paul G Green, Douglas R Balachandran, Siddharth Journal Article United States Cell. 2020 Mar 19;180(6):1115-1129.e13. doi: 10.1016/j.cell.2020.02.050.