title: Caspase-11 stimulates rapid flagellin-independent pyroptosis in response to Legionella pneumophila.
abstract: A flagellin-independent caspase-1 activation pathway that does not require NAIP5 or NRLC4 is induced by the intracellular pathogen Legionella pneumophila. Here we demonstrate that this pathway requires caspase-11. Treatment of macrophages with LPS up-regulated the host components required for this caspase-11 activation pathway. Activation by Legionella differed from caspase-11 activation using previously described agonists in that Legionella caspase-11 activation was rapid and required bacteria with a functional type IV secretion system called Dot/Icm. Legionella activation of caspase-11 induced pyroptosis by a mechanism independent of the NAIP/NLRC4 and caspase-1 axis. Legionella activation of caspase-11 stimulated activation of caspase-1 through NLRP3 and ASC. Induction of caspase-11-dependent responses occurred in macrophages deficient in the adapter proteins TRIF or MyD88 but not in macrophages deficient in both signaling factors. Although caspase-11 was produced in macrophages deficient in the type-I IFN receptor, there was a severe defect in caspase-11-dependent pyroptosis in these cells. These data indicate that macrophages respond to microbial signatures to produce proteins that mediate a capsase-11 response and that the caspase-11 system provides an alternative pathway for rapid detection of an intracellular pathogen capable of evading the canonical caspase-1 activation system that responds to bacterial flagellin.
authors: Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT 06536, USA.
authors: Christopher L
authors: CL
authors: Case
authors: Lara J
authors: LJ
authors: Kohler
authors: Jonilson B
authors: JB
authors: Lima
authors: Till
authors: T
authors: Strowig
authors: Marcel R
authors: MR
authors: de Zoete
authors: Richard A
authors: RA
authors: Flavell
authors: Dario S
authors: DS
authors: Zamboni
authors: Craig R
authors: CR
authors: Roy
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D001854:Bone Marrow Cells / Q000378:metabolism / Q000382:microbiology; D053468:CARD Signaling Adaptor Proteins; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D020170:Caspase 1 / Q000235:genetics / Q000378:metabolism; D020169:Caspases / Q000235:genetics / Q000378:metabolism*; D053471:Caspases, Initiator; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation; D005408:Flagellin / Q000235:genetics / Q000378:metabolism*; D054884:Host-Pathogen Interactions; D015151:Immunoblotting; D016952:Legionella pneumophila / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D008264:Macrophages / Q000166:cytology / Q000378:metabolism* / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009336:Necrosis; D053633:Receptor, Interferon alpha-beta / Q000235:genetics / Q000378:metabolism
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D020170:Caspase 1; D020169:Caspases; D053471:Caspases, Initiator; D016207:Cytokines; D003598:Cytoskeletal Proteins; D005408:Flagellin; D053594:Myeloid Differentiation Factor 88; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D053633:Receptor, Interferon alpha-beta; C508032:Ifnar1 protein, mouse; C512299:Ipaf protein, mouse; C507780:Myd88 protein, mouse; C492716:Nlrp3 protein, mouse; C498534:Pycard protein, mouse; C476286:Ticam1 protein, mouse; C101136:Casp4 protein, mouse