Differential Activation of the Inflammasome by caspase-1 Adaptors ASC and Ipaf

Nature. 2004 Jul 8;430(6996):213-8. doi: 10.1038/nature02664. Epub 2004 Jun 9.

Abstract

Specific adaptors regulate the activation of initiator caspases; for example, FADD and Apaf-1 engage caspases 8 and 9, respectively. The adaptors ASC, Ipaf and RIP2 have each been proposed to regulate caspase-1 (also called interleukin (IL)-1 converting enzyme), which is activated within the 'inflammasome', a complex comprising several adaptors. Here we show the impact of ASC-, Ipaf- or RIP2-deficiency on inflammasome function. ASC was essential for extracellular ATP-driven activation of caspase-1 in toll-like receptor (TLR)-stimulated macrophages. Accordingly, ASC-deficient macrophages exhibited defective maturation of IL-1beta and IL-18, and ASC-null mice were resistant to lipopolysaccharide-induced endotoxic shock. Furthermore, activation of caspase-1 in response to an intracellular pathogen (Salmonella typhimurium) was abrogated severely in ASC-null macrophages. Unexpectedly, Ipaf-deficient macrophages activated caspase-1 in response to TLR plus ATP stimulation but not S. typhimurium. Caspase-1 activation was not compromised by loss of RIP2. These data show that whereas ASC is key to caspase-1 activation within the inflammasome, Ipaf provides a special conduit to the inflammasome for signals triggered by intracellular pathogens. Notably, cell death triggered by stimuli that engage caspase-1 was ablated in macrophages lacking either ASC or Ipaf, suggesting a coupling between the inflammatory and cell death pathways.

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Adenosine Triphosphate / pharmacology
  • Animals
  • Calcium-Binding Proteins / genetics
  • Calcium-Binding Proteins / metabolism*
  • Caspase 1 / metabolism*
  • Cell Death
  • Enzyme Activation / drug effects
  • Gene Deletion
  • Inflammation / enzymology*
  • Inflammation / immunology
  • Interleukin-1 / metabolism
  • Interleukin-18 / metabolism
  • Lipopolysaccharides / pharmacology
  • Macrophages, Peritoneal / cytology
  • Macrophages, Peritoneal / enzymology
  • Macrophages, Peritoneal / metabolism
  • Macrophages, Peritoneal / microbiology
  • Mice
  • Protein Processing, Post-Translational / drug effects
  • Protein-Serine-Threonine Kinases / deficiency
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Receptor-Interacting Protein Serine-Threonine Kinase 2
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Salmonella typhimurium / physiology
  • Shock, Septic / enzymology
  • Shock, Septic / metabolism
  • Shock, Septic / microbiology
  • Shock, Septic / pathology

Substances

  • Calcium-Binding Proteins
  • Interleukin-1
  • Interleukin-18
  • Lipopolysaccharides
  • Adenosine Triphosphate
  • Protein-Serine-Threonine Kinases
  • Receptor-Interacting Protein Serine-Threonine Kinase 2
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Ripk2 protein, mouse
  • Caspase 1