Agostini Laetitia, Martinon Fabio, Burns Kimberly, McDermott Michael F, Hawkins Philip N, Tschopp Jürg
Department of Biochemistry, University of Lausanne, Chemin des Boveresses 155, CH-1066 Epalinges, Switzerland.
Immunity. 2004 Mar;20(3):319-25. doi: 10.1016/s1074-7613(04)00046-9.
Mutations within the NALP3/cryopyrin/CIAS1 gene are responsible for three autoinflammatory disorders: Muckle-Wells syndrome, familial cold autoinflammatory syndrome, and CINCA. The NALP3 protein is homologous to NALP1, which is a component of the inflammasome, a molecular platform that activates the proinflammatory caspases-1 and -5. NALP3 (and other members of the NALP family) lacks the C-terminal, CARD-containing sequence of NALP1, and its role in caspase activation is unclear. Here, we report that NALP2 and NALP3 associate with ASC, the CARD-containing protein Cardinal, and caspase-1 (but not caspase-5), thereby forming an inflammasome with high proIL-1beta-processing activity. Macrophages from Muckle-Wells patients spontaneously secrete active IL-1beta. Increased inflammasome activity is therefore likely to be the molecular basis of the symptoms associated with NALP3-dependent autoinflammatory disorders.
NALP3/cryopyrin/CIAS1基因内的突变导致三种自身炎症性疾病：穆克-韦尔斯综合征、家族性冷自身炎症综合征和慢性婴儿神经皮肤关节综合征。NALP3蛋白与NALP1同源，NALP1是炎性小体的一个组成部分，炎性小体是一个激活促炎性半胱天冬酶-1和-5的分子平台。NALP3（以及NALP家族的其他成员）缺乏NALP1含CARD的C末端序列，其在半胱天冬酶激活中的作用尚不清楚。在此，我们报告NALP2和NALP3与ASC、含CARD的蛋白Cardinal以及半胱天冬酶-1（而非半胱天冬酶-5）相互作用，从而形成具有高proIL-1β加工活性的炎性小体。穆克-韦尔斯患者的巨噬细胞自发分泌活性IL-1β。因此，炎性小体活性增加可能是与NALP3依赖性自身炎症性疾病相关症状的分子基础。
