NALP3 forms an IL-1beta-processing inflammasome with increased activity in Muckle-Wells autoinflammatory disorder

Immunity. 2004 Mar;20(3):319-25. doi: 10.1016/s1074-7613(04)00046-9.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing*
  • Autoimmune Diseases / enzymology
  • Autoimmune Diseases / immunology*
  • CARD Signaling Adaptor Proteins
  • Carrier Proteins / chemistry
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Caspase 1 / metabolism
  • Cell Line
  • Cells, Cultured
  • Cytoskeletal Proteins / metabolism
  • Humans
  • Inflammation / enzymology
  • Inflammation / immunology
  • Interleukin-1 / metabolism*
  • Macromolecular Substances
  • Macrophages / immunology
  • Mutation
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Neoplasm Proteins / chemistry
  • Neoplasm Proteins / metabolism
  • Protein Precursors / metabolism*
  • Protein Structure, Tertiary


  • Adaptor Proteins, Signal Transducing
  • CARD Signaling Adaptor Proteins
  • CARD8 protein, human
  • Carrier Proteins
  • Cytoskeletal Proteins
  • Interleukin-1
  • Macromolecular Substances
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NLRP3 protein, human
  • Neoplasm Proteins
  • PYCARD protein, human
  • Protein Precursors
  • interleukin 1 precursor
  • Caspase 1