Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 104, Issue 19, Pages 8041-8046Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0611496104
Keywords
inflammation; IL-1 beta
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Funding
- NCRR NIH HHS [K12RR023248, K12 RR023248] Funding Source: Medline
- NIAID NIH HHS [R01AI057157, R01 AI063031, R01AI063031, U54 AI057157, T32 AI007151, T32AI007151] Funding Source: Medline
- NIDCR NIH HHS [R01DE16326, R01 DE016326] Funding Source: Medline
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The CATERPILLER (CLR/NLR) gene family encodes a family of putative nucleotide-binding proteins important for host defense. Although nucleoticle binding is thought to be central to this family, this aspect is largely unstudied. The CATERPILLER protein cryopyrin/NALP3 regulates IL-1 beta processing by assembling the multimeric inflammasome complex. Mutations within the exon encoding the nucleotide-binding domain are associated with hereditary periodic fevers characterized by constitutive IL-1 beta production. We demonstrate that purified cryopyrin binds ATP, dATP, and ATP-agarose, but not CTP, GTP, or UITP, and exhibits ATPase activity. Mutation of the nucleotide-binding domain reduces ATP binding, caspase-1 activation, IL-1 beta production, cell death, macromolecular complex formation, self-association, and association with the inflammasome component ASC. Disruption of nucleoticle binding abolishes the constitutive activation of disease-associated mutants, identifying nucleoticle binding by cryopyrin as a potential target for antiinflammatory pharmacologic intervention.
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