title: Caspase-8 mediates caspase-1 processing and innate immune defense in response to bacterial blockade of NF-κB and MAPK signaling.
abstract: Toll-like receptor signaling and subsequent activation of NF-κB- and MAPK-dependent genes during infection play an important role in antimicrobial host defense. The YopJ protein of pathogenic Yersinia species inhibits NF-κB and MAPK signaling, resulting in blockade of NF-κB-dependent cytokine production and target cell death. Nevertheless, Yersinia infection induces inflammatory responses in vivo. Moreover, increasing the extent of YopJ-dependent cytotoxicity induced by Yersinia pestis and Yersinia pseudotuberculosis paradoxically leads to decreased virulence in vivo, suggesting that cell death promotes anti-Yersinia host defense. However, the specific pathways responsible for YopJ-induced cell death and how this cell death mediates immune defense against Yersinia remain poorly defined. YopJ activity induces processing of multiple caspases, including caspase-1, independently of inflammasome components or the adaptor protein ASC. Unexpectedly, caspase-1 activation in response to the activity of YopJ required caspase-8, receptor-interacting serine/threonine kinase 1 (RIPK1), and Fas-associated death domain (FADD), but not RIPK3. Furthermore, whereas RIPK3 deficiency did not affect YopJ-induced cell death or caspase-1 activation, deficiency of both RIPK3 and caspase-8 or FADD completely abrogated Yersinia-induced cell death and caspase-1 activation. Mice lacking RIPK3 and caspase-8 in their hematopoietic compartment showed extreme susceptibility to Yersinia and were deficient in monocyte and neutrophil-derived production of proinflammatory cytokines. Our data demonstrate for the first time to our knowledge that RIPK1, FADD, and caspase-8 are required for YopJ-induced cell death and caspase-1 activation and suggest that caspase-8-mediated cell death overrides blockade of immune signaling by YopJ to promote anti-Yersinia immune defense.
authors.affiliation: Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104;Institute for Immunology and ibrodsky@vet.upenn.edu nphilip@mail.med.upenn.edu.
authors.forename: Naomi H
authors.initials: NH
authors.lastname: Philip
authors.affiliation: Departments of Immunology and.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Dillon
authors.affiliation: Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104;
authors.forename: Annelise G
authors.initials: AG
authors.lastname: Snyder
authors.affiliation: Departments of Immunology and.
authors.forename: Patrick
authors.initials: P
authors.lastname: Fitzgerald
authors.affiliation: Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104;
authors.forename: Meghan A
authors.initials: MA
authors.lastname: Wynosky-Dolfi
authors.affiliation: Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104;
authors.forename: Erin E
authors.initials: EE
authors.lastname: Zwack
authors.affiliation: Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104;
authors.forename: Baofeng
authors.initials: B
authors.lastname: Hu
authors.affiliation: Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104;
authors.forename: Louise
authors.initials: L
authors.lastname: Fitzgerald
authors.affiliation: Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104;
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Mauldin
authors.affiliation: Department of Microbiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104;
authors.forename: Alan M
authors.initials: AM
authors.lastname: Copenhaver
authors.affiliation: Department of Microbiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104;
authors.forename: Sunny
authors.initials: S
authors.lastname: Shin
authors.affiliation: Department of Biostatistics and Bioinformatics, Roswell Park Cancer Institute, Buffalo, NY 14263; and.
authors.forename: Lei
authors.initials: L
authors.lastname: Wei
authors.affiliation: Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105;
authors.forename: Matthew
authors.initials: M
authors.lastname: Parker
authors.affiliation: Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105;
authors.forename: Jinghui
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Immunology, University of Washington, Seattle, WA 98109.
authors.forename: Andrew
authors.initials: A
authors.lastname: Oberst
authors.affiliation: Departments of Immunology and.
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Green
authors.affiliation: Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104;Institute for Immunology and ibrodsky@vet.upenn.edu nphilip@mail.med.upenn.edu.
authors.forename: Igor E
authors.initials: IE
authors.lastname: Brodsky
mesh_terms: D000818:Animals; D017209:Apoptosis; D001426:Bacterial Proteins / Q000235:genetics; D020170:Caspase 1 / Q000378:metabolism*; D053181:Caspase 8 / Q000378:metabolism*; D004789:Enzyme Activation; D053200:Fas-Associated Death Domain Protein / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D007113:Immunity, Innate; D020935:MAP Kinase Signaling System; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism*; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism; D015009:Yersinia Infections / Q000382:microbiology; D015011:Yersinia pseudotuberculosis
chemical_list: D001426:Bacterial Proteins; C505534:Fadd protein, mouse; D053200:Fas-Associated Death Domain Protein; D016328:NF-kappa B; C109227:YopP protein, Yersinia; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C506251:Ripk1 protein, mouse; C505526:Casp8 protein, mouse; D053181:Caspase 8; D020170:Caspase 1
keywords: apoptosis; innate immunity; macrophage; programmed necrosis; pyroptosis