Abstract
Generation of Interleukin (IL)-1beta via cleavage of its proform requires the activity of caspase-1 (and caspase-11 in mice), but the mechanism involved in the activation of the proinflammatory caspases remains elusive. Here we report the identification of a caspase-activating complex that we call the inflammasome. The inflammasome comprises caspase-1, caspase-5, Pycard/Asc, and NALP1, a Pyrin domain-containing protein sharing structural homology with NODs. Using a cell-free system, we show that proinflammatory caspase activation and proIL-1beta processing is lost upon prior immunodepletion of Pycard. Moreover, expression of a dominant-negative form of Pycard in differentiated THP-1 cells blocks proIL-1beta maturation and activation of inflammatory caspases induced by LPS in vivo. Thus, the inflammasome constitutes an important arm of the innate immunity.
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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Apoptosis Regulatory Proteins
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Blotting, Western
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CARD Signaling Adaptor Proteins
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Caspase 1 / metabolism
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Caspases / metabolism*
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Cell Line
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Cell-Free System
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Cytoskeletal Proteins / genetics
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Cytoskeletal Proteins / metabolism*
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Enzyme Activation
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HeLa Cells
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Humans
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Inflammation / enzymology*
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Inflammation / metabolism
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Interleukin-1 / metabolism*
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Lipopolysaccharides / pharmacology
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Macromolecular Substances
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NLR Proteins
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Protein Precursors / metabolism*
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Protein Processing, Post-Translational* / drug effects
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Proteins / metabolism*
Substances
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Adaptor Proteins, Signal Transducing
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Apoptosis Regulatory Proteins
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CARD Signaling Adaptor Proteins
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Cytoskeletal Proteins
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Interleukin-1
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Lipopolysaccharides
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Macromolecular Substances
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NLR Proteins
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NLRP1 protein, human
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PYCARD protein, human
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Protein Precursors
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Proteins
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CASP5 protein, human
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Caspases
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Caspase 1