title: NLRP3 recruitment by NLRC4 during Salmonella infection.
abstract: NLRC4 and NLRP3, of the NOD-like receptor (NLR) family of intracellular proteins, are expressed in innate immune cells and are thought to nucleate distinct inflammasome complexes that promote caspase-1 activation, secretion of the proinflammatory cytokines IL-1β and IL-18, and a form of cell death termed pyroptosis. We show that NLRP3 associates with NLRC4 in macrophages infected with Salmonella typhimurium or transfected with flagellin. The significance of the interaction between the NLRC4 NACHT domain and NLRP3 was revealed when Nlrc4(S533A/S533A) bone marrow-derived macrophages (BMDMs) expressing phosphorylation site mutant NLRC4 S533A had only a mild defect in caspase-1 activation when compared with NLRC4-deficient BMDMs. NLRC4 S533A activated caspase-1 by recruiting NLRP3 and its adaptor protein ASC. Thus, Nlrc4(S533A/S533A) Nlrp3(-/-) BMDMs more closely resembled Nlrc4(-/-) BMDMs in their response to S. typhimurium or flagellin. The interplay between NLRP3 and NLRC4 reveals an unexpected overlap between what had been considered distinct inflammasome scaffolds.
authors.affiliation: Department of Physiological Chemistry, Genentech Inc., South San Francisco, CA 94080.
authors.forename: Yan
authors.initials: Y
authors.lastname: Qu
authors.affiliation: Department of Early Stage Cell Culture, Genentech Inc., South San Francisco, CA 94080.
authors.forename: Shahram
authors.initials: S
authors.lastname: Misaghi
authors.affiliation: Department of Physiological Chemistry, Genentech Inc., South San Francisco, CA 94080.
authors.forename: Kim
authors.initials: K
authors.lastname: Newton
authors.affiliation: Department of Physiological Chemistry, Genentech Inc., South San Francisco, CA 94080.
authors.forename: Allie
authors.initials: A
authors.lastname: Maltzman
authors.affiliation: Department of Protein Chemistry, Genentech Inc., South San Francisco, CA 94080.
authors.forename: Anita
authors.initials: A
authors.lastname: Izrael-Tomasevic
authors.affiliation: Department of Protein Chemistry, Genentech Inc., South San Francisco, CA 94080.
authors.forename: David
authors.initials: D
authors.lastname: Arnott
authors.affiliation: Department of Physiological Chemistry, Genentech Inc., South San Francisco, CA 94080 dixit@gene.com.
authors.forename: Vishva M
authors.initials: VM
authors.lastname: Dixit
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000276:immunology*; D001854:Bone Marrow Cells / Q000378:metabolism* / Q000382:microbiology; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000276:immunology*; D005408:Flagellin / Q000235:genetics / Q000276:immunology; D008264:Macrophages / Q000276:immunology* / Q000382:microbiology; D051379:Mice; D018345:Mice, Knockout; D020125:Mutation, Missense; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000235:genetics / Q000276:immunology*; D000072417:Protein Domains; D012480:Salmonella Infections / Q000235:genetics / Q000276:immunology*; D012486:Salmonella typhimurium / Q000235:genetics / Q000276:immunology*
chemical_list: D051017:Apoptosis Regulatory Proteins; D002135:Calcium-Binding Proteins; C512299:Ipaf protein, mouse; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D005408:Flagellin