Influenza Virus Z-RNAs Induce ZBP1-Mediated Necroptosis

  • Cell. 2020 Mar 19;180(6):1115-1129.e13. doi: 10.1016/j.cell.2020.02.050.
Ting Zhang  1 ,  Chaoran Yin  1 ,  David F Boyd  2 ,  Giovanni Quarato  2 ,  Justin P Ingram  1 ,  Maria Shubina  1 ,  Katherine B Ragan  3 ,  Takumi Ishizuka  4 ,  Jeremy Chase Crawford  2 ,  Bart Tummers  2 ,  Diego A Rodriguez  2 ,  Jia Xue  5 ,  Suraj Peri  1 ,  William J Kaiser  6 ,  Carolina B López  5 ,  Yan Xu  4 ,  Jason W Upton  3 ,  Paul G Thomas  2 ,  Douglas R Green  2 ,  Siddharth Balachandran  7
Affiliations
  • 1. Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA, USA.
  • 2. Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • 3. Department of Molecular Biosciences, LaMontagne Center for Infectious Disease, University of Texas, Austin, Austin, TX, USA.
  • 4. Division of Chemistry, Department of Medical Sciences, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan.
  • 5. Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 6. University of Texas Health Sciences Center, San Antonio, San Antonio, TX, USA.
  • 7. Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA, USA. Electronic address: [email protected].
PMID: 32200799 DOI: 10.1016/j.cell.2020.02.050
Abstract

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.

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