title: NALP3 forms an IL-1beta-processing inflammasome with increased activity in Muckle-Wells autoinflammatory disorder.
abstract: Mutations within the NALP3/cryopyrin/CIAS1 gene are responsible for three autoinflammatory disorders: Muckle-Wells syndrome, familial cold autoinflammatory syndrome, and CINCA. The NALP3 protein is homologous to NALP1, which is a component of the inflammasome, a molecular platform that activates the proinflammatory caspases-1 and -5. NALP3 (and other members of the NALP family) lacks the C-terminal, CARD-containing sequence of NALP1, and its role in caspase activation is unclear. Here, we report that NALP2 and NALP3 associate with ASC, the CARD-containing protein Cardinal, and caspase-1 (but not caspase-5), thereby forming an inflammasome with high proIL-1beta-processing activity. Macrophages from Muckle-Wells patients spontaneously secrete active IL-1beta. Increased inflammasome activity is therefore likely to be the molecular basis of the symptoms associated with NALP3-dependent autoinflammatory disorders.
authors.affiliation: Department of Biochemistry, University of Lausanne, Chemin des Boveresses 155, CH-1066 Epalinges, Switzerland.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Agostini
authors.forename: Fabio
authors.initials: F
authors.lastname: Martinon
authors.forename: Kimberly
authors.initials: K
authors.lastname: Burns
authors.forename: Michael F
authors.initials: MF
authors.lastname: McDermott
authors.forename: Philip N
authors.initials: PN
authors.lastname: Hawkins
authors.forename: Jürg
authors.initials: J
authors.lastname: Tschopp
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D001327:Autoimmune Diseases / Q000201:enzymology / Q000276:immunology*; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020170:Caspase 1 / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000201:enzymology / Q000276:immunology; D007375:Interleukin-1 / Q000378:metabolism*; D046911:Macromolecular Substances; D008264:Macrophages / Q000276:immunology; D009154:Mutation; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009363:Neoplasm Proteins / Q000737:chemistry / Q000378:metabolism; D011498:Protein Precursors / Q000378:metabolism*; D017434:Protein Structure, Tertiary
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D053468:CARD Signaling Adaptor Proteins; C455623:CARD8 protein, human; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D007375:Interleukin-1; D046911:Macromolecular Substances; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D009363:Neoplasm Proteins; C402202:PYCARD protein, human; D011498:Protein Precursors; C043830:interleukin 1 precursor; D020170:Caspase 1