Structural mechanism for NEK7-licensed activation of NLRP3 inflammasome
Structural mechanism for NEK7-licensed activation of NLRP3 inflammasome
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NEK7 许可的 NLRP3 炎症小体激活的结构机制
DOI：
10.1038/s41586-019-1295-z
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发表时间：
2019-06-20
期刊：
影响因子：
64.8
通讯作者：
Wu, Hao
中科院分区：
文献类型：
--
作者：
Sharif, Humayun;Wang, Li;Wu, Hao
NLRP3炎症小体可被包括尼日利亚菌素、尿酸晶体、β-淀粉样纤维和细胞外ATP在内的刺激物激活。有丝分裂激酶NEK7在间期许可NLRP3炎症小体的组装和激活。在此我们报道了处于非活性状态的人NLRP3与NEK7复合物的冷冻电镜结构，分辨率为3.8埃。耳环状的NLRP3由弯曲的富含亮氨酸重复序列结构域和球状的NACHT结构域组成，NEK7的C末端叶与NLRP3的两个结构域相贴合。NLRP3和NEK7之间的结构识别通过体外和细胞内的诱变得到证实。基于NLRC4炎症小体对活性NLRP3 - NEK7构象进行建模，预测与NLRP3结合的NEK7和相邻NLRP3之间存在额外的接触。对该界面的突变消除了NEK7或NLRP3在NEK7敲除或NLRP3敲除细胞中挽救NLRP3激活的能力。这些数据表明，NEK7通过两部分相互作用连接相邻的NLRP3亚基，以介导NLRP3炎症小体的激活。
The NLRP3 inflammasome can be activated by stimuli that include nigericin, uric acid crystals, amyloid-beta fibrils and extracellnlar ATP. The mitotic kinase NEK7 licenses the assembly and activation of the NLRP3 inflammasome in interphase. Here we report a cryo-electron microscopy structure of inactive human NLRP3 in complex with NEK7, at a resolution of 3.8 angstrom. The earring-shaped NLRP3 consists of curved leucine -rich-repeat and globular NACHT domains, and the C-terminal lobe of NEK7 nestles against both NLRP3 domains. Structural recognition between NLRP3 and NEK7 is confirmed by mutagenesis both in vitro and in cells. Modelling of an active NLRP3-NEK7 conformation based on the NLRC4 inflammasome predicts an additional contact between an NLRP3-bound NEK7 and a neighbouring NLRP3. Mutations to this interface abolish the ability of NEK7 or NLRP3 to rescue NLRP3 activation in NEK7-knockout or NLRP3-knockout cells. These data suggest that NEK7 bridges adjacent NLRP3 subunits with bipartite interactions to mediate the activation of the NLRP3 inflammasome.