Inflammasomes are cytosolic innate immune complexes that activate caspase-1 upon detection of pathogenic and endogenous dangers^1-5, and NLRP3 is an inflammasome sensor of membrane damage highly important in inducing inflammation^2,6,7. Here we report cryo-EM structures of disk-shaped active NLRP3 oligomers in complex with ATP𝛾S, the centrosomal kinase NEK7, and the adaptor protein ASC which recruits caspase-1. In these NLRP3-NEK7-ASC complexes, the central NACHT domain of NLRP3 assumes an ATP-bound conformation in which two of its subdomains rotate by ~85 ° relative to the ADP-bound inactive conformation^8-12. The FISNA domain conserved in NLRP3 but absent in most NLRPs¹³ becomes ordered in its key regions to stabilize the active NACHT conformation and mediate most interactions in the disk. Mutations on these interactions compromise NLRP3-mediated caspase-1 activation. The N-terminal PYDs from all the NLRP3 subunits gather together to form a PYD filament that recruits ASC PYD to elicit downstream signalling. Surprisingly, the C-terminal LRR domain and the LRR-bound NEK7 do not participate in disk interfaces. Together with previous structures of inactive NLRP3 cage in which LRR-LRR interactions play an important role^8-11, we propose that the role of NEK7 is to break the inactive cage to transform NLRP3 into the active NLRP3 inflammasome disk.

炎症小体是细胞质先天免疫复合物，在检测到致病性和内源性危险时会激活 caspase-1 ^1-5 ，而 NLRP3 是膜损伤的炎症小体传感器，对于诱导炎症非常重要^2,6,7 。在这里，我们报道了与 ATP𝛾S、中心体激酶 NEK7 和招募 caspase-1 的接头蛋白 ASC 复合的盘状活性 NLRP3 寡聚物的冷冻电镜结构。在这些 NLRP3-NEK7-ASC 复合物中，NLRP3 的中央 NACHT 结构域呈现 ATP 结合构象，其中两个子结构域相对于 ADP 结合非活性构象旋转约 85° ^8-12 。 FISNA 结构域在 NLRP3 中保守，但在大多数 NLRP 中不存在¹³在其关键区域变得有序，以稳定活性 NACHT 构象并介导盘中的大多数相互作用。这些相互作用的突变会损害 NLRP3 介导的 caspase-1 激活。所有 NLRP3 亚基的 N 端 PYD 聚集在一起形成 PYD 丝，招募 ASC PYD 以引发下游信号传导。令人惊讶的是，C 端 LRR 域和 LRR 结合的 NEK7 不参与磁盘接口。结合以前的失活NLRP3笼结构（其中LRR-LRR相互作用发挥重要作用^8-11） ，我们提出NEK7的作用是打破失活笼，将NLRP3转化为活性NLRP3炎性体盘。