Influenza Virus Z-RNAs Induce ZBP1-Mediated Necroptosis

Ting Zhang, Chaoran Yin, David F. Boyd, Giovanni Quarato, Justin P. Ingram, Maria Shubina, Katherine B. Ragan, Takumi Ishizuka, Jeremy Chase Crawford, Bart Tummers, Diego A. Rodriguez, Jia Xue, Suraj Peri, William J. Kaiser, Carolina B. López, Yan Xu, Jason W. Upton, Paul G. Thomas, Douglas R. Green, Siddharth Balachandran

Research output: Contribution to journalArticlepeer-review

189 Scopus citations


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.

Original languageEnglish
Pages (from-to)1115-1129.e13
Issue number6
StatePublished - Mar 19 2020


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


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