Cryopyrin activates the inflammasome in response to toxins and ATP View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2006-03

AUTHORS

Sanjeev Mariathasan, David S. Weiss, Kim Newton, Jacqueline McBride, Karen O'Rourke, Meron Roose-Girma, Wyne P. Lee, Yvette Weinrauch, Denise M. Monack, Vishva M. Dixit

ABSTRACT

A crucial part of the innate immune response is the assembly of the inflammasome, a cytosolic complex of proteins that activates caspase-1 to process the proinflammatory cytokines interleukin (IL)-1beta and IL-18. The adaptor protein ASC is essential for inflammasome function, binding directly to caspase-1 (refs 3, 4), but the triggers of this interaction are less clear. ASC also interacts with the adaptor cryopyrin (also known as NALP3 or CIAS1). Activating mutations in cryopyrin are associated with familial cold autoinflammatory syndrome, Muckle-Wells syndrome and neonatal onset multisystem inflammatory disease, diseases that are characterized by excessive production of IL-1beta. Here we show that cryopyrin-deficient macrophages cannot activate caspase-1 in response to Toll-like receptor agonists plus ATP, the latter activating the P2X7 receptor to decrease intracellular K+ levels. The release of IL-1beta in response to nigericin, a potassium ionophore, and maitotoxin, a potent marine toxin, was also found to be dependent on cryopyrin. In contrast to Asc-/- macrophages, cells deficient in the gene encoding cryopyrin (Cias1-/-) activated caspase-1 and secreted normal levels of IL-1beta and IL-18 when infected with Gram-negative Salmonella typhimurium or Francisella tularensis. Macrophages exposed to Gram-positive Staphylococcus aureus or Listeria monocytogenes, however, required both ASC and cryopyrin to activate caspase-1 and secrete IL-1beta. Therefore, cryopyrin is essential for inflammasome activation in response to signalling pathways triggered specifically by ATP, nigericin, maitotoxin, S. aureus or L. monocytogenes. More... »

PAGES

228

Journal

TITLE

Nature

ISSUE

7081

VOLUME

440

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/nature04515

DOI

http://dx.doi.org/10.1038/nature04515

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1025852033

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/16407890


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