Differential activation of the inflammasome by caspase-1 adaptors ASC and Ipaf.
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.
Pubmed ID: 15190255 RIS Download
Adenosine Triphosphate | Animals | Calcium-Binding Proteins | Caspase 1 | Cell Death | Enzyme Activation | Gene Deletion | Inflammation | Interleukin-1 | Interleukin-18 | Lipopolysaccharides | Macrophages, Peritoneal | Mice | Protein Processing, Post-Translational | Protein-Serine-Threonine Kinases | Receptor-Interacting Protein Serine-Threonine Kinase 2 | Receptor-Interacting Protein Serine-Threonine Kinases | Salmonella typhimurium | Shock, Septic