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Cell. 2020 Mar 19;180(6):1115-1129.e13. doi: 10.1016/j.cell.2020.02.050.

Influenza Virus Z-RNAs Induce ZBP1-Mediated Necroptosis.

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Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA, USA.
Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA.
Department of Molecular Biosciences, LaMontagne Center for Infectious Disease, University of Texas, Austin, Austin, TX, USA.
Division of Chemistry, Department of Medical Sciences, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan.
Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA.
University of Texas Health Sciences Center, San Antonio, San Antonio, TX, USA.
Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA, USA. Electronic address:


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.


MLKL; RIPK3; Z-RNA; ZBP1; apoptosis; caspase-8; dsRNA; influenza; necroptosis


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