Regulation of cryopyrin/Pypaf1 signaling by pyrin, the familial Mediterranean fever gene product

Biochem Biophys Res Commun. 2003 Mar 14;302(3):575-80. doi: 10.1016/s0006-291x(03)00221-3.


Cryopyrin, a member of the Nod protein family mutated in familial cold urticaria and Muckle-Wells syndrome, has been recently implicated in inflammation. However, the mechanism of activation and regulation of the cryopyrin signaling pathway remains poorly understood. We report here that co-expression of cryopyrin with its binding partner, ASC, induced both apoptosis and NF-kappaB activation. This signaling was mimicked by oligomerization of ASC, suggesting that cryopyrin activates downstream targets as reported for other Nod family members. Notably, pyrin, the product of the familial Mediterranean fever gene, inhibited cryopyrin-mediated apoptosis and NF-kappaB activation by disrupting the cryopyrin-ASC interaction. These results provide evidence for a cryopyrin signaling pathway activated through the induced proximity of ASC, which is negatively regulated by pyrin.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Apoptosis
  • Blood Proteins / metabolism*
  • CARD Signaling Adaptor Proteins
  • Carrier Proteins / metabolism*
  • Cell Line
  • Cytoskeletal Proteins / metabolism
  • DNA, Complementary / metabolism
  • Familial Mediterranean Fever / genetics*
  • Gene Expression Regulation*
  • Humans
  • Molecular Sequence Data
  • NF-kappa B / metabolism
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Plasmids / metabolism
  • Precipitin Tests
  • Protein Binding
  • Protein Structure, Tertiary
  • Proteins / metabolism*
  • Pyrin
  • Signal Transduction*
  • Transfection


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

Associated data

  • GENBANK/AF389420
  • GENBANK/AY226382