Bacterial RNA and small antiviral compounds activate caspase-1 through cryopyrin/Nalp3
Bacterial RNA and small antiviral compounds activate caspase-1 through cryopyrin/Nalp3
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DOI：
10.1038/nature04517
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发表时间：
2006-03-09
期刊：
影响因子：
64.8
通讯作者：
Núñez, G
中科院分区：
文献类型：
--
作者：
Kanneganti, TD;Özören, N;Núñez, G
CIAS1基因错义突变导致三种自体炎症障碍：家族性感冒自体炎症综合征、Muckle-Wells综合征和新生儿起病的多系统炎症性疾病(1)。低温蛋白(也称为NALP3)是CIAS1的产物，是NOD-LRR蛋白家族的成员，与细胞内宿主防御信号通路(2，3)的激活有关。低温比林形成一个被称为“炎症体”的多蛋白质复合体，它含有凋亡相关的斑点样蛋白(ASC)和caspase-1，并促进caspase-1的激活和前白介素1β(ref.4)。在这里，我们展示了低温比林缺乏对炎症体功能和免疫反应的影响。在细菌RNA和咪唑喹啉化合物R837和R848的反应中，低温比林和ASC对于caspase-1的激活和IL-1β和IL-18的产生是必不可少的。相反，低温比林缺乏对肿瘤坏死因子-α和IL-6的分泌以及核因子-kappaB和丝裂原活化蛋白激酶(MAPKs)的激活没有影响。此外，我们还发现Toll样受体和低温比林通过不同的细胞内途径控制IL-1β和IL-18的分泌。这些结果揭示了低温比林通过细菌RNA介导的caspase-1活化在宿主防御中的关键作用，并为自体炎症综合征的发病机制提供了见解。
Missense mutations in the CIAS1 gene cause three autoinflammatory disorders: familial cold autoinflammatory syndrome, Muckle-Wells syndrome and neonatal-onset multiple-system inflammatory disease(1). Cryopyrin (also called Nalp3), the product of CIAS1, is a member of the NOD-LRR protein family that has been linked to the activation of intracellular host defence signalling pathways(2,3). Cryopyrin forms a multi-protein complex termed 'the inflammasome', which contains the apoptosis-associated speck-like protein (ASC) and caspase-1, and promotes caspase-1 activation and processing of pro-interleukin (IL)-1 beta (ref. 4). Here we show the effect of cryopyrin deficiency on inflammasome function and immune responses. Cryopyrin and ASC are essential for caspase-1 activation and IL-1 beta and IL-18 production in response to bacterial RNA and the imidazoquinoline compounds R837 and R848. In contrast, secretion of tumour-necrosis factor-alpha and IL-6, as well as activation of NF-kappa B and mitogen-activated protein kinases (MAPKs) were unaffected by cryopyrin deficiency. Furthermore, we show that Toll-like receptors and cryopyrin control the secretion of IL-1 beta and IL-18 through different intracellular pathways. These results reveal a critical role for cryopyrin in host defence through bacterial RNA-mediated activation of caspase-1, and provide insights regarding the pathogenesis of autoinflammatory syndromes.