title: Cytoplasmic flagellin activates caspase-1 and secretion of interleukin 1beta via Ipaf.
abstract: Macrophages respond to Salmonella typhimurium infection via Ipaf, a NACHT-leucine-rich repeat family member that activates caspase-1 and secretion of interleukin 1beta. However, the specific microbial salmonella-derived agonist responsible for activating Ipaf is unknown. We show here that cytosolic bacterial flagellin activated caspase-1 through Ipaf but was independent of Toll-like receptor 5, a known flagellin sensor. Stimulation of the Ipaf pathway in macrophages after infection required a functional salmonella pathogenicity island 1 type III secretion system but not the flagellar type III secretion system; furthermore, Ipaf activation could be recapitulated by the introduction of purified flagellin directly into the cytoplasm. These observations raise the possibility that the salmonella pathogenicity island 1 type III secretion system cannot completely exclude 'promiscuous' secretion of flagellin and that the host capitalizes on this 'error' by activating a potent host-defense pathway.
authors.affiliation: Institute for Systems Biology, Seattle, Washington 98103, USA.
authors.forename: Edward A
authors.initials: EA
authors.lastname: Miao
authors.forename: Celia M
authors.initials: CM
authors.lastname: Alpuche-Aranda
authors.forename: Monica
authors.initials: M
authors.lastname: Dors
authors.forename: April E
authors.initials: AE
authors.lastname: Clark
authors.forename: Martin W
authors.initials: MW
authors.lastname: Bader
authors.forename: Samuel I
authors.initials: SI
authors.lastname: Miller
authors.forename: Alan
authors.initials: A
authors.lastname: Aderem
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000502:physiology*; D001426:Bacterial Proteins / Q000235:genetics / Q000276:immunology; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000502:physiology*; D020170:Caspase 1 / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism / Q000382:microbiology; D004789:Enzyme Activation; D005408:Flagellin / Q000235:genetics / Q000276:immunology*; D007375:Interleukin-1 / Q000378:metabolism*; D008264:Macrophages / Q000201:enzymology / Q000276:immunology / Q000382:microbiology; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D021381:Protein Transport; D012480:Salmonella Infections / Q000201:enzymology / Q000235:genetics / Q000276:immunology*; D012486:Salmonella typhimurium / Q000235:genetics / Q000276:immunology / Q000472:pathogenicity*; D051198:Toll-Like Receptor 5 / Q000235:genetics / Q000502:physiology
chemical_list: D051017:Apoptosis Regulatory Proteins; D001426:Bacterial Proteins; D002135:Calcium-Binding Proteins; C094427:FljB protein, Salmonella; D007375:Interleukin-1; C512299:Ipaf protein, mouse; D051198:Toll-Like Receptor 5; D005408:Flagellin; D020170:Caspase 1