DAI Senses Influenza A Virus Genomic RNA and Activates RIPK3-Dependent Cell Death

Cell Host Microbe. 2016 Nov 9;20(5):674-681. doi: 10.1016/j.chom.2016.09.014. Epub 2016 Oct 13.


Influenza A virus (IAV) is an RNA virus that is cytotoxic to most cell types in which it replicates. IAV activates the host kinase RIPK3, which induces cell death via parallel pathways of necroptosis, driven by the pseudokinase MLKL, and apoptosis, dependent on the adaptor proteins RIPK1 and FADD. How IAV activates RIPK3 remains unknown. We report that DAI (ZBP1/DLM-1), previously implicated as a cytoplasmic DNA sensor, is essential for RIPK3 activation by IAV. Upon infection, DAI recognizes IAV genomic RNA, associates with RIPK3, and is required for recruitment of MLKL and RIPK1 to RIPK3. Cells lacking DAI or containing DAI mutants deficient in nucleic acid binding are resistant to IAV-triggered necroptosis and apoptosis. DAI-deficient mice fail to control IAV replication and succumb to lethal respiratory infection. These results identify DAI as a link between IAV replication and RIPK3 activation and implicate DAI as a sensor of RNA viruses.

MeSH terms

  • Animals
  • Cell Death*
  • Cell Line
  • Gene Knockout Techniques
  • Genomics
  • Glycoproteins / deficiency
  • Glycoproteins / metabolism*
  • Host-Pathogen Interactions*
  • Influenza A virus / immunology*
  • Mice
  • Mice, Knockout
  • Mutation
  • Protein Kinases / metabolism
  • RNA, Viral / metabolism*
  • RNA-Binding Proteins
  • Receptor-Interacting Protein Serine-Threonine Kinases / metabolism*


  • Glycoproteins
  • RNA, Viral
  • RNA-Binding Proteins
  • Zbp1 protein, mouse
  • MLKL protein, mouse
  • Protein Kinases
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Ripk1 protein, mouse
  • Ripk3 protein, mouse