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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing*
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Autoimmune Diseases / enzymology
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Autoimmune Diseases / immunology*
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CARD Signaling Adaptor Proteins
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Carrier Proteins / chemistry
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Carrier Proteins / genetics
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Carrier Proteins / metabolism*
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Caspase 1 / metabolism
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Cell Line
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Cells, Cultured
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Cytoskeletal Proteins / metabolism
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Humans
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Inflammation / enzymology
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Inflammation / immunology
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Interleukin-1 / metabolism*
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Macromolecular Substances
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Macrophages / immunology
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Mutation
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NLR Family, Pyrin Domain-Containing 3 Protein
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Neoplasm Proteins / chemistry
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Neoplasm Proteins / metabolism
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Protein Precursors / metabolism*
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Protein Structure, Tertiary
Substances
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Adaptor Proteins, Signal Transducing
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CARD Signaling Adaptor Proteins
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CARD8 protein, human
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Carrier Proteins
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Cytoskeletal Proteins
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Interleukin-1
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Macromolecular Substances
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NLR Family, Pyrin Domain-Containing 3 Protein
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NLRP3 protein, human
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Neoplasm Proteins
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PYCARD protein, human
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Protein Precursors
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interleukin 1 precursor
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Caspase 1