Cryopyrin and pyrin activate caspase-1, but not NF-kappaB, via ASC oligomerization

Cell Death Differ. 2006 Feb;13(2):236-49. doi: 10.1038/sj.cdd.4401734.


Mutations in cryopyrin and pyrin proteins are responsible for several autoinflammatory disorders in humans, suggesting that these proteins play important roles in regulating inflammation. Using a HEK293 cell-based reconstitution system that stably expresses ASC and procaspase-1 we demonstrated that neither cryopyrin nor pyrin or their corresponding disease-associated mutants could significantly activate NF-kappaB in this system. However, both cryopyrin and two disease-associated cryopyrin mutants induced ASC oligomerization and ASC-dependent caspase-1 activation, with the disease-associated mutants being more potent than the wild-type (WT) cryopyrin, because of increased self-oligomerization. Contrary to the proposed anti-inflammatory activity of WT pyrin, our results demonstrated that pyrin, like cryopyrin, can also assemble an inflammasome complex with ASC and procaspase-1 leading to ASC oligomerization, caspase-1 activation and interleukin-1beta processing. Thus, we propose that pyrin could function as a proinflammatory molecule.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Baculoviridae
  • CARD Signaling Adaptor Proteins
  • Carrier Proteins / genetics
  • Carrier Proteins / physiology*
  • Caspase 1 / genetics
  • Caspase 1 / metabolism*
  • Cell Line
  • Cytoskeletal Proteins / chemistry
  • Cytoskeletal Proteins / genetics
  • Cytoskeletal Proteins / physiology*
  • Enzyme Activation
  • Gene Expression Regulation
  • Humans
  • Immunoprecipitation
  • Inflammation / genetics
  • Inflammation / physiopathology
  • Microscopy, Confocal
  • Mutation
  • NF-kappa B / genetics
  • NF-kappa B / physiology*
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Protein Structure, Tertiary
  • Pyrin


  • CARD Signaling Adaptor Proteins
  • Carrier Proteins
  • Cytoskeletal Proteins
  • MEFV protein, human
  • NF-kappa B
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NLRP3 protein, human
  • PYCARD protein, human
  • Pyrin
  • Caspase 1