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.
Mariathasan
Sanjeev
S
Molecular Oncology Department, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
Newton
Kim
K
Monack
Denise M
DM
Vucic
Domagoj
D
French
Dorothy M
DM
Lee
Wyne P
WP
Roose-Girma
Meron
M
Erickson
Sharon
S
Dixit
Vishva M
VM
D000255:Adenosine Triphosphate / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020170:Caspase 1 / Q000378:metabolism*; D016923:Cell Death; D004789:Enzyme Activation / Q000187:drug effects; D017353:Gene Deletion; D007249:Inflammation / Q000201:enzymology* / Q000276:immunology; D007375:Interleukin-1 / Q000378:metabolism; D020382:Interleukin-18 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000201:enzymology / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D012486:Salmonella typhimurium / Q000502:physiology; D012772:Shock, Septic / Q000201:enzymology / Q000378:metabolism / Q000382:microbiology / Q000473:pathology
D002135:Calcium-Binding Proteins; D007375:Interleukin-1; D020382:Interleukin-18; D008070:Lipopolysaccharides; D000255:Adenosine Triphosphate; D017346:Protein Serine-Threonine Kinases; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C506255:Ripk2 protein, mouse; D020170:Caspase 1