Cryopyrin/NALP3 Binds ATP/dATP, is an ATPase, and Requires ATP Binding to Mediate Inflammatory Signaling

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2007 May 8

PMID 17483456

Citations 236

Authors

Joseph A Duncan

Daniel T Bergstralh

Yanhong Wang

Stephen B Willingham

Zhengmao Ye

Albert G Zimmermann

Jenny Pan-Yun Ting

Affiliations

Soon will be listed here.

Abstract

The CATERPILLER (CLR/NLR) gene family encodes a family of putative nucleotide-binding proteins important for host defense. Although nucleotide binding is thought to be central to this family, this aspect is largely unstudied. The CATERPILLER protein cryopyrin/NALP3 regulates IL-1beta 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-1beta production. We demonstrate that purified cryopyrin binds ATP, dATP, and ATP-agarose, but not CTP, GTP, or UTP, and exhibits ATPase activity. Mutation of the nucleotide-binding domain reduces ATP binding, caspase-1 activation, IL-1beta production, cell death, macromolecular complex formation, self-association, and association with the inflammasome component ASC. Disruption of nucleotide binding abolishes the constitutive activation of disease-associated mutants, identifying nucleotide binding by cryopyrin as a potential target for antiinflammatory pharmacologic intervention.

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