NALP3 forms an IL-lβ-Processing inflammasome with increased activity in Muckle-Wells autoinflammatory disorder
NALP3 forms an IL-lβ-Processing inflammasome with increased activity in Muckle-Wells autoinflammatory disorder
复制标题
DOI：
10.1016/s1074-7613(04)00046-9
复制
发表时间：
2004-03-01
期刊：
影响因子：
32.4
通讯作者：
Tschopp, J
中科院分区：
文献类型：
--
作者：
Agostini, L;Martinon, F;Tschopp, J
NALP3/cryopyrin/CIAS1基因突变可导致三种自身炎症性疾病：Muckle-Wells综合征、家族性感冒自身炎症综合征和CINCA。NALP3蛋白同源于NALP1，后者是炎性小体的一个组成部分，炎性小体是激活促炎caspase -1和-5的分子平台。NALP3（以及NALP家族的其他成员）缺乏NALP1的c端，含有card的序列，其在caspase激活中的作用尚不清楚。在这里，我们报道NALP2和NALP3与ASC、含card蛋白Cardinal和caspase-1（但不包括caspase-5）结合，从而形成具有高proil -1 β加工活性的炎性体。Muckle-Wells患者的巨噬细胞自发分泌活性il -1 β。因此，炎性体活性增加可能是nalp3依赖性自身炎症性疾病相关症状的分子基础。
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 proinflarnmatory 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.