title: Differential requirement for Caspase-1 autoproteolysis in pathogen-induced cell death and cytokine processing.
abstract: Activation of the cysteine protease Caspase-1 is a key event in the innate immune response to infections. Synthesized as a proprotein, Caspase-1 undergoes autoproteolysis within multiprotein complexes called inflammasomes. Activated Caspase-1 is required for proteolytic processing and for release of the cytokines interleukin-1β and interleukin-18, and it can also cause rapid macrophage cell death. We show that macrophage cell death and cytokine maturation in response to infection with diverse bacterial pathogens can be separated genetically and that two distinct inflammasome complexes mediate these events. Inflammasomes containing the signaling adaptor Asc form a single large "focus" in which Caspase-1 undergoes autoproteolysis and processes IL-1β/IL-18. In contrast, Asc-independent inflammasomes activate Caspase-1 without autoproteolysis and do not form any large structures in the cytosol. Caspase-1 mutants unable to undergo autoproteolysis promoted rapid cell death, but processed IL-1β/18 inefficiently. Our results suggest the formation of spatially and functionally distinct inflammasomes complexes in response to bacterial pathogens.
authors.affiliation: Department of Microbiology and Immunology, Stanford School of Medicine, Stanford University, Stanford, CA 94305, USA.
authors.forename: Petr
authors.initials: P
authors.lastname: Broz
authors.forename: Jakob
authors.initials: J
authors.lastname: von Moltke
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Jones
authors.forename: Russell E
authors.initials: RE
authors.lastname: Vance
authors.forename: Denise M
authors.initials: DM
authors.lastname: Monack
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000502:physiology; D001424:Bacterial Infections / Q000378:metabolism / Q000473:pathology; D053468:CARD Signaling Adaptor Proteins / Q000502:physiology; D002135:Calcium-Binding Proteins / Q000502:physiology; D020170:Caspase 1 / Q000235:genetics / Q000502:physiology*; D016923:Cell Death; D002460:Cell Line; D016207:Cytokines / Q000502:physiology*; D003598:Cytoskeletal Proteins / Q000502:physiology; D004268:DNA-Binding Proteins; D005603:Francisella / Q000502:physiology; D058847:Inflammasomes / Q000502:physiology; D016952:Legionella pneumophila / Q000502:physiology; D008264:Macrophages / Q000378:metabolism / Q000382:microbiology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011550:Pseudomonas aeruginosa / Q000502:physiology; D012486:Salmonella typhimurium / Q000502:physiology
chemical_list: C540422:Aim2 protein, mouse; D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002135:Calcium-Binding Proteins; D016207:Cytokines; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D058847:Inflammasomes; C512299:Ipaf protein, mouse; D009687:Nuclear Proteins; C498534:Pycard protein, mouse; D020170:Caspase 1