头条焦点：活化NLRP3炎性小体盘的冷冻电镜结构获解析

美国哈佛大学吴皓研究组报道活化NLRP3炎性小体盘的冷冻电镜。该项研究成果于2022年11月28日在线发表在《自然》杂志上。

研究人员报告了盘状活化NLRP3寡聚体与ATPγS、中心体激酶NEK7和招募caspase-1的适配器蛋白ASC复合后的冷冻EM结构。在这些NLRP3-NEK7-ASC复合物中，NLRP3的中心NACHT结构域呈现出ATP结合的构象，其中两个子结构域相对于ADP结合的非活化构象旋转了约85°。在NLRP3中保守但在大多数NLRP中没有的FISNA结构域在其关键区域变得有序，从而稳定活跃的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影响了NLRP3介导的caspase-1激活。来自所有NLRP3亚基的N端PYD聚集在一起，形成一个PYD丝，招募ASC PYD来激发下游信号。

令人惊讶的是，C端LRR结构域和LRR结合的NEK7不参与盘状界面。结合以前的非活化NLRP3笼的结构（其中LRR-LRR相互作用发挥了重要作用），研究人员提出NEK7的作用是打破非活化笼，将NLRP3转化为活化的NLRP3炎性小体盘。

(资料图)

据介绍，炎性小体是细胞膜先天免疫复合物，在检测到致病性和内源性危险时激活caspase-1，而NLRP3是炎性小体的膜损伤传感器，在诱发炎症方面非常重要。

附：英文原文

Title: Cryo-EM structures of the active NLRP3 inflammasome disk

Author: Xiao, Le, Magupalli, Venkat Giri, Wu, Hao

Issue&Volume: 2022-11-28

Abstract: Inflammasomes are cytosolic innate immune complexes that activate caspase-1 upon detection of pathogenic and endogenous dangers1-5, and NLRP3 is an inflammasome sensor of membrane damage highly important in inducing inflammation2,6,7. Here we report cryo-EM structures of disk-shaped active NLRP3 oligomers in complex with ATP??S, 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 conformation8-12. 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 role8-11, we propose that the role of NEK7 is to break the inactive cage to transform NLRP3 into the active NLRP3 inflammasome disk.

DOI: 10.1038/s41586-022-05570-8

Source: https://www.nature.com/articles/s41586-022-05570-8

来源：科学网 小柯机器人

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