美国哈佛大学吴皓研究团队发现，NLRP3笼控制通路激活。2021年12月2日，《细胞》杂志在线发表了这项成果。

研究人员报告了全长小鼠NLRP3的内源性、刺激反应形式是一个由LRR-LRR相互作用固定在一起的12-16体的双环笼，其中的pyrin结构域被屏蔽在结构内以避免过早激活。令人惊讶的是，这种NLRP3形式主要是膜定位的，这与以前注意到的NLRP3在各种膜细胞器的定位是一致的。

结构引导的诱变显示，跨高尔基体网络分散到囊泡中，这是许多NLRP3激活刺激物的早期事件，需要NLRP3的双环笼子。双环缺陷的NLRP3突变体废除了炎症体灶点的形成、caspase-1加工和细胞死亡。因此，这些数据揭示了膜上的一个生理性NLRP3寡聚体，它准备好感知各种信号来诱导炎症体的激活。

据介绍，NLRP3正在成为细胞内膜完整性的重要炎症体传感器和对抗慢性炎症的高度重要临床靶标。

附：英文原文

Title: NLRP3 cages revealed by full-length mouse NLRP3 structure control pathway activation

Author: Liudmila Andreeva, Liron David, Shaun Rawson, Chen Shen, Teerithveen Pasricha, Pablo Pelegrin, Hao Wu

Issue&Volume: 2021-12-02

Abstract: The NACHT-, leucine-rich-repeat- (LRR), and pyrin domain-containing protein 3 (NLRP3)is emerging to be a critical intracellular inflammasome sensor of membrane integrityand a highly important clinical target against chronic inflammation. Here, we reportthat an endogenous, stimulus-responsive form of full-length mouse NLRP3 is a 12- to16-mer double-ring cage held together by LRR-LRR interactions with the pyrin domainsshielded within the assembly to avoid premature activation. Surprisingly, this NLRP3form is predominantly membrane localized, which is consistent with previously notedlocalization of NLRP3 at various membrane organelles. Structure-guided mutagenesisreveals that trans-Golgi network dispersion into vesicles, an early event observed for many NLRP3-activatingstimuli, requires the double-ring cages of NLRP3. Double-ring-defective NLRP3 mutantsabolish inflammasome punctum formation, caspase-1 processing, and cell death. Thus,our data uncover a physiological NLRP3 oligomer on the membrane that is poised tosense diverse signals to induce inflammasome activation.

DOI: 10.1016/j.cell.2021.11.011

Source: https://www.cell.com/cell/fulltext/S0092-8674(21)01326-X