RIPK3 Activates Parallel Pathways of MLKL-Driven Necroptosis and FADD-Mediated Apoptosis to Protect against Influenza A Virus

• Type of Material: Article
• Authors: Shoko Nogusa, Fox Chase Cancer Center; Roshan J Thapa, Fox Chase Cancer Center; Christopher P. Dillon, St. Jude Children’s Research Hospital; Swantje Liedmann, St. Jude Children’s Research Hospital; Thomas H. Oguin, St. Jude Children’s Research Hospital; Justin P. Ingram, Fox Chase Cancer Center; Diego A. Rodriguez, St. Jude Children’s Research Hospital; Rachelle Kosoff, Fox Chase Cancer Center; Shalini Sharma, St. Jude Children’s Research Hospital; Oliver Sturm, St. Jude Children’s Research Hospital; Katherine Verbist, St. Jude Children’s Research Hospital; Peter J. Gough, GlaxoSmithKline; John Bertin, GlaxoSmithKline; Boris M. Hartmann, Icahn School of Medicine at Mt. Sinai; Stuart C. Sealfon, Icahn School of Medicine at Mt. Sinai; William Kaiser, Emory University; Edward Mocarski, Emory University; Carolina B. Lopez, University of Pennsylvania; Paul G. Thomas, St. Jude Children’s Research Hospital; Andrew Oberst, University of Washington; Douglas R. Green, St. Jude Children’s Research Hospital; Siddharth Balachandran, Fox Chase Cancer Center
• Language: English
• Date: 2016-07-13
• Publisher: Elsevier (Cell Press)
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2016 Elsevier Inc.
• Final Published Version (URL): http://dx.doi.org/10.1016/j.chom.2016.05.011
• Title of Journal or Parent Work: Cell Host and Microbe
• ISSN: 1931-3128
• Volume: 20
• Issue: 1
• Start Page: 13
• End Page: 24
• Grant/Funding Information: Additional funds were provided by the F.M. Kirby Foundation, and via NIH Cancer Center Support Grant P30CA006927 to SB.; This work was supported by NIAID contract HHSN272201400006C (St. Jude Center of Excellence for Influenza Research and Surveillance) to PGT, NIH grant AI109472 to CBL, NIH grants AI44828 and CA169291 to DRG, and NIH grants CA168621, CA190542 and AI113469 to SB.
• Keywords: MICE; NLRP3 INFLAMMASOME; SIGNALING PATHWAY; RESPONSES; Life Sciences & Biomedicine; Parasitology; PROGRAMMED NECROSIS; INFECTION; IN-VIVO; TARGET; Microbiology; Science & Technology; Virology; CELL-DEATH; KINASE INHIBITORS
• Research Categories: Health Sciences, Immunology; Biology, Virology

Abstract

Influenza A virus (IAV) is a lytic virus in primary cultures of many cell types and in vivo. We report that the kinase RIPK3 is essential for IAV-induced lysis of mammalian fibroblasts and lung epithelial cells. Replicating IAV drives assembly of a RIPK3-containing complex that includes the kinase RIPK1, the pseudokinase MLKL, and the adaptor protein FADD, and forms independently of signaling by RNA-sensing innate immune receptors (RLRs, TLRs, PKR), or the cytokines type I interferons and TNF-α. Downstream of RIPK3, IAV activates parallel pathways of MLKL-driven necroptosis and FADD-mediated apoptosis, with the former reliant on RIPK3 kinase activity and neither on RIPK1 activity. Mice deficient in RIPK3 or doubly deficient in MLKL and FADD, but not MLKL alone, are more susceptible to IAV than their wild-type counterparts, revealing an important role for RIPK3-mediated apoptosis in antiviral immunity. Collectively, these results outline RIPK3-activated cytolytic mechanisms essential for controlling respiratory IAV infection.