Gumucio D L, Diaz A, Schaner P, Richards N, Babcock C, Schaller M, Cesena T
Department of Cell and Developmental Biology, University of Michigan, Ann Arbor 48109-0616, USA.
Clin Exp Rheumatol. 2002 Jul-Aug;20(4 Suppl 26):S45-53.
The genetic bases for several human autoinflammatory syndromes have recently been identified, and the mutated proteins responsible for these diseases are rapidly being characterized. Here, we examine two of these newly identified proteins, pyrin (also called marenostrin, product of the familial Mediterranean fever locus, MEFV) and cryopyrin (product of the CAIS1 locus, and mutated in familial cold urticaria, Muckle Wells syndrome and chronic infantile neurological cutaneous and articular syndrome). Both pyrin and cryopyrin contain an N-terminal domain that encodes a death domain-related structure, now known as the pyrin domain, or PyD. We trace the molecular interactions mediated by these PyDs, examine the evolution of the family of molecules containing this domain, and discuss the function of PyD-containing proteins and their homologues. Synthesis of the available data indicates that both pyrin and cryopyrin interact via their PyDs with a common adaptor protein, ASC. ASC itself participates in at least three important cellular processes: apoptosis, recruitment and activation of pro-caspase-1 (with associated processing and secretion of IL-1beta), and activation of NF-kappaB (a transcription factor involved in both initiation and resolution of the inflammatory response). Through PyD:PyD interactions, pyrin and cryopyrin, as well as several related, but still uncharacterized PyD containing proteins, appear to modulate the activity of all three of these processes, each of which plays a crucial role in the inflammatory pathways that characterize the innate immune system.
最近已确定了几种人类自身炎症综合征的遗传基础，并且正在迅速对导致这些疾病的突变蛋白进行表征。在此，我们研究其中两种新发现的蛋白，即pyrin（也称为marenostrin，家族性地中海热基因座MEFV的产物）和cryopyrin（CAIS1基因座的产物，在家族性寒冷性荨麻疹、穆克-韦尔斯综合征和慢性婴儿神经皮肤和关节综合征中发生突变）。pyrin和cryopyrin都含有一个N端结构域，该结构域编码一种与死亡结构域相关的结构，现在称为pyrin结构域或PyD。我们追踪由这些PyD介导的分子相互作用，研究包含该结构域的分子家族的进化，并讨论含PyD蛋白及其同源物的功能。对现有数据的综合分析表明，pyrin和cryopyrin都通过其PyD与一种共同的衔接蛋白ASC相互作用。ASC自身至少参与三个重要的细胞过程：凋亡、前半胱天冬酶-1的募集和激活（伴随IL-1β的加工和分泌）以及NF-κB的激活（一种参与炎症反应起始和消退的转录因子）。通过PyD:PyD相互作用，pyrin和cryopyrin以及几种相关但仍未表征的含PyD蛋白似乎调节这三个过程的活性，每个过程在表征先天免疫系统的炎症途径中都起着关键作用。
