Cryopyrin/NALP3 binds ATP/dATP, is an ATPase, and requires ATP binding to mediate inflammatory signaling
Cryopyrin/NALP3 binds ATP/dATP, is an ATPase, and requires ATP binding to mediate inflammatory signaling
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DOI：
10.1073/pnas.0611496104
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发表时间：
2007-05-08
影响因子：
11.1
通讯作者：
Ting, Jenny Pan-Yun
中科院分区：
文献类型：
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作者：
Duncan, Joseph A.;Bergstralht, Daniel T.;Ting, Jenny Pan-Yun
CATERPILLER（CLR/NLR）基因家族编码一类对宿主防御具有重要作用的假定核苷酸结合蛋白。尽管核苷酸结合被认为是该家族的核心特性，但这方面在很大程度上尚未得到研究。CATERPILLER蛋白cryopyrin/NALP3通过组装多聚体炎症小体复合物来调节白细胞介素 -1β（IL -1β）的加工过程。编码核苷酸结合结构域的外显子内的突变与以持续性IL -1β产生为特征的遗传性周期性发热相关。我们证明，纯化的cryopyrin可结合ATP、dATP以及ATP - 琼脂糖，但不结合CTP、GTP或UTP，并且具有ATP酶活性。核苷酸结合结构域的突变会降低ATP结合、半胱天冬酶 -1（caspase -1）活化、IL -1β产生、细胞死亡、大分子复合物形成、自身结合以及与炎症小体成分ASC的结合。核苷酸结合的破坏消除了疾病相关突变体的持续性激活，这表明cryopyrin的核苷酸结合可作为抗炎药物干预的潜在靶点。
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.