The Inflammasome: A Molecular Platform Triggering Activation of Inflammatory Caspases and Processing of proIL-beta

Mol Cell. 2002 Aug;10(2):417-26. doi: 10.1016/s1097-2765(02)00599-3.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing*
  • Apoptosis Regulatory Proteins
  • Blotting, Western
  • CARD Signaling Adaptor Proteins
  • Caspase 1 / metabolism
  • Caspases / metabolism*
  • Cell Line
  • Cell-Free System
  • Cytoskeletal Proteins / genetics
  • Cytoskeletal Proteins / metabolism*
  • Enzyme Activation
  • HeLa Cells
  • Humans
  • Inflammation / enzymology*
  • Inflammation / metabolism
  • Interleukin-1 / metabolism*
  • Lipopolysaccharides / pharmacology
  • Macromolecular Substances
  • Protein Precursors / metabolism*
  • Protein Processing, Post-Translational* / drug effects
  • Proteins / metabolism*

Substances

  • Adaptor Proteins, Signal Transducing
  • Apoptosis Regulatory Proteins
  • CARD Signaling Adaptor Proteins
  • Cytoskeletal Proteins
  • Interleukin-1
  • Lipopolysaccharides
  • Macromolecular Substances
  • NLRP1 protein, human
  • PYCARD protein, human
  • Protein Precursors
  • Proteins
  • CASP5 protein, human
  • Caspases
  • Caspase 1