Differential activation of the inflammasome by caspase-1 adaptors ASC and Ipaf

Sanjeev Mariathasan, Kim Newton, Denise M. Monack, Domagoj Vucic, Dorothy M. French, Wyne P. Lee, Meron Roose-Girma, Sharon Erickson and Vishva M. Dixit ()
Additional contact information
Sanjeev Mariathasan: Genentech, Inc.
Kim Newton: Genentech, Inc.
Denise M. Monack: Stanford School of Medicine
Domagoj Vucic: Genentech, Inc.
Dorothy M. French: Genentech, Inc.
Wyne P. Lee: Genentech, Inc.
Meron Roose-Girma: Genentech, Inc.
Sharon Erickson: Genentech, Inc.
Vishva M. Dixit: Genentech, Inc.

Nature, 2004, vol. 430, issue 6996, 213-218

Abstract: Abstract Specific adaptors regulate the activation of initiator caspases; for example, FADD and Apaf-1 engage caspases 8 and 9, respectively1. 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 adaptors2. 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-1β 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.

Date: 2004
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DOI: 10.1038/nature02664

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