2. Academic Validation
  3. DAI Senses Influenza A Virus Genomic RNA and Activates RIPK3-Dependent Cell Death

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.
Roshan J Thapa 1,  Justin P Ingram 1,  Katherine B Ragan 2,  Shoko Nogusa 1,  David F Boyd 3,  Asiel A Benitez 4,  Haripriya Sridharan 2,  Rachelle Kosoff 1,  Maria Shubina 1,  Vanessa J Landsteiner 2,  Mark Andrake 1,  Peter Vogel 3,  Luis J Sigal 5,  Benjamin R tenOever 4,  Paul G Thomas 3,  Jason W Upton 6,  Siddharth Balachandran 7
Affiliations

Affiliations

  • 1 Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
  • 2 Department of Molecular Biosciences, LaMontagne Center for Infectious Disease, University of Texas, Austin, TX 78712, USA.
  • 3 Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
  • 4 Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • 5 Department of Microbiology and Immunology, Thomas Jefferson School of Medicine, Philadelphia, PA 19107, USA.
  • 6 Department of Molecular Biosciences, LaMontagne Center for Infectious Disease, University of Texas, Austin, TX 78712, USA. Electronic address: upton@austin.utexas.edu.
  • 7 Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA. Electronic address: siddharth.balachandran@fccc.edu.
PMID: 27746097 DOI: 10.1016/j.chom.2016.09.014
Abstract

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.

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