RIPK3 Activates Parallel Pathways of MLKL-Driven Necroptosis and FADD-Mediated Apoptosis to Protect against Influenza A Virus.
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.
Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Shoko
S
Nogusa
Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Roshan J
RJ
Thapa
Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Christopher P
CP
Dillon
Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Swantje
S
Liedmann
Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Thomas H
TH
Oguin
Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Justin P
JP
Ingram
Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Diego A
DA
Rodriguez
Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Rachelle
R
Kosoff
Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Shalini
S
Sharma
Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Oliver
O
Sturm
Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Katherine
K
Verbist
Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area, GlaxoSmithKline, Collegeville, PA 19426, USA.
Peter J
PJ
Gough
Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area, GlaxoSmithKline, Collegeville, PA 19426, USA.
John
J
Bertin
Department of Neurology, Icahn School of Medicine at Mt. Sinai, New York, NY 10029, USA.
Boris M
BM
Hartmann
Department of Neurology, Icahn School of Medicine at Mt. Sinai, New York, NY 10029, USA.
Stuart C
SC
Sealfon
Emory Vaccine Center, Emory University, Atlanta, GA 30322, USA.
William J
WJ
Kaiser
Emory Vaccine Center, Emory University, Atlanta, GA 30322, USA.
Edward S
ES
Mocarski
School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Carolina B
CB
López
Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Paul G
PG
Thomas
Department of Microbiology and Immunology, University of Washington, Seattle, WA 98109, USA.
Andrew
A
Oberst
Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. Electronic address: douglas.green@stjude.org.
Douglas R
DR
Green
Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA. Electronic address: siddharth.balachandran@fccc.edu.
Siddharth
S
Balachandran
D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000502:physiology / Q000821:virology; D053200:Fas-Associated Death Domain Protein / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000502:physiology / Q000821:virology; D006801:Humans; D009980:Influenza A virus / Q000254:growth & development* / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D009336:Necrosis; D009976:Orthomyxoviridae Infections / Q000473:pathology; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D055503:Protein Multimerization; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*
C505534:Fadd protein, mouse; D053200:Fas-Associated Death Domain Protein; C570694:MLKL protein, mouse; D011494:Protein Kinases; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C506251:Ripk1 protein, mouse; C485615:Ripk3 protein, mouse