title: DAI Senses Influenza A Virus Genomic RNA and Activates RIPK3-Dependent Cell Death.
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.
authors.affiliation: Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
authors.forename: Roshan J
authors.initials: RJ
authors.lastname: Thapa
authors.affiliation: Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
authors.forename: Justin P
authors.initials: JP
authors.lastname: Ingram
authors.affiliation: Department of Molecular Biosciences, LaMontagne Center for Infectious Disease, University of Texas, Austin, TX 78712, USA.
authors.forename: Katherine B
authors.initials: KB
authors.lastname: Ragan
authors.affiliation: Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
authors.forename: Shoko
authors.initials: S
authors.lastname: Nogusa
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: David F
authors.initials: DF
authors.lastname: Boyd
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Asiel A
authors.initials: AA
authors.lastname: Benitez
authors.affiliation: Department of Molecular Biosciences, LaMontagne Center for Infectious Disease, University of Texas, Austin, TX 78712, USA.
authors.forename: Haripriya
authors.initials: H
authors.lastname: Sridharan
authors.affiliation: Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
authors.forename: Rachelle
authors.initials: R
authors.lastname: Kosoff
authors.affiliation: Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Shubina
authors.affiliation: Department of Molecular Biosciences, LaMontagne Center for Infectious Disease, University of Texas, Austin, TX 78712, USA.
authors.forename: Vanessa J
authors.initials: VJ
authors.lastname: Landsteiner
authors.affiliation: Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Andrake
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Vogel
authors.affiliation: Department of Microbiology and Immunology, Thomas Jefferson School of Medicine, Philadelphia, PA 19107, USA.
authors.forename: Luis J
authors.initials: LJ
authors.lastname: Sigal
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Benjamin R
authors.initials: BR
authors.lastname: tenOever
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Paul G
authors.initials: PG
authors.lastname: Thomas
authors.affiliation: Department of Molecular Biosciences, LaMontagne Center for Infectious Disease, University of Texas, Austin, TX 78712, USA. Electronic address: upton@austin.utexas.edu.
authors.forename: Jason W
authors.initials: JW
authors.lastname: Upton
authors.affiliation: Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA. Electronic address: siddharth.balachandran@fccc.edu.
authors.forename: Siddharth
authors.initials: S
authors.lastname: Balachandran
mesh_terms: D000818:Animals; D016923:Cell Death; D002460:Cell Line; D055786:Gene Knockout Techniques; D023281:Genomics; D006023:Glycoproteins / Q000172:deficiency / Q000378:metabolism*; D054884:Host-Pathogen Interactions; D009980:Influenza A virus / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D011494:Protein Kinases / Q000378:metabolism; D012367:RNA, Viral / Q000378:metabolism*; D016601:RNA-Binding Proteins; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D006023:Glycoproteins; D012367:RNA, Viral; D016601:RNA-Binding Proteins; C402632:Zbp1 protein, mouse; C570694:MLKL protein, mouse; D011494:Protein Kinases; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C506251:Ripk1 protein, mouse; C485615:Ripk3 protein, mouse