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首页> 外文期刊>Journal of Molecular Biology >Mechanisms of NLRP1-Mediated Autoinflammatory Disease in Humans and Mice
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Mechanisms of NLRP1-Mediated Autoinflammatory Disease in Humans and Mice

机译：NLRP1介导的人和小鼠的NLRP1介导的自身炎性疾病的机制

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Abstract NLRP1 was the first NOD-like receptor described to form an inflammasome, recruiting ASC to activate caspase-1, which processes interleukin-1β and interleukin-18 to their active form. A wealth of new genetic information has now redefined our understanding of this innate immune sensor. Specifically, rare loss-of-function variants in the N-terminal pyrin domain indicate that this part of NLRP1 is autoinhibitory and normally acts to prevent a familial autoinflammatory skin disease associated with cancer. In the absence of a ligand to trigger human NLRP1, these mutations have now confirmed the requirement of NLRP1 autolytic cleavage within the FIIND domain, which had previously been implicated in NLRP1 activation. Autolytic cleavage generates a C-terminal fragment of NLRP1 containing the CARD domain which then forms an ASC-dependent inflammasome. The CARD domain as an inflammasome linker is consistent with the observation that under some conditions, particularly for mouse NLRP1, caspase-1 can be engaged directly, and although it is no longer processed, it is still capable of producing mature IL-1β. Additional rare variants in a linker region between the LRR and FIIND domains of NLRP1 also cause autoinflammatory disease in both humans and mice. This new genetic information is likely to provide for more mechanistic insight in the years to come, contributing to our understanding of how NLRP1 functions as an innate immune sensor of infection and predisposes to autoimmune or autoinflammatory diseases. Graphical abstract Display Omitted Highlights ? Genetic variants in NLRP1 lead to autoimmune and autoinflammatory diseases in both humans and mice. ? NLRP1 N-terminal domain (PYD in humans) is autoinhibitory, whereas the C-terminal cleavage fragment containing the CARD domain engages an ASC-dependent inflammasome. ? Disease-associated mutations in the NLRP1 linker region between NACHT and LRR domains suggest additional mechanisms of autoinhibition.
机译：摘要NLRP1是第一个形成的NOD样受体，其形成炎性炎症，募集ASC以激活Caspase-1，其将白细胞介素-1β和白细胞介素-18加入其活性形式。丰富的新遗传信息现在已经重新定义了我们对本天生免疫传感器的理解。具体地，N-末端吡喃域中的罕见函数变体表明NLRP1的这一部分是自动抑制的，通常是为了防止与癌症相关的家族性炎症性皮肤病。在不存在触发人NLRP1的情况下，这些突变现在已经证实了在网域内的NLRP1自水解切割的要求，其先前涉及NLRP1活化。自溶解乳化产生含有卡片结构域的NLRP1的C末端片段，然后形成ASC依赖性炎症。作为炎症组接头的卡片域与观察结果一致，即在某些条件下，特别是对于小鼠NLRP1，Caspase-1可以直接接合，并且尽管它不再加工，但它仍然能够产生成熟的IL-1β。在NLRP1的LRR和FIID结构域之间的接头区域中的额外罕见变体也会导致人和小鼠中的自身炎症性疾病。这种新的遗传信息可能会在未来几年内提供更具机制的洞察力，促进我们对NLRP1如何作为感染的先天免疫传感器和自身免疫或自身炎症疾病的易用。图形抽象显示省略了亮点？ NLRP1中的遗传变异导致人和小鼠的自身免疫和自身炎性疾病。还是NLRP1 N末端域（人体中的PYD）是自动抑制的，而含有卡片域的C末端切割片段接合ASC依赖性炎症。还是NACHT和LRR结构域之间NLRP1接头区域中的疾病相关突变表明了自动抑制的额外机制。

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