The nucleotide-binding domain and leucine-rich-repeat (LRR) containing protein 3 with a pyrin domain (NLRP3) is emerging to be a critical intracellular inflammasome sensor of membrane integrity and a highly important clinical target against chronic inflammation. Here we report that the endogenous, stimulus-responsive form of full-length NLRP3 is a 12-16 mer double ring cage held together by LRR-LRR interactions with the pyrin domains shielded within the assembly to avoid premature activation. Surprisingly, this NLRP3 form is predominantly membrane localized, which is consistent with previously noted localization of NLRP3 at various membrane organelles. Structure-guided mutagenesis reveals that trans-Golgi network dispersion into vesicles, an early event observed for all NLRP3 activating stimuli, requires the double ring cages of NLRP3. Double ring-defective NLRP3 mutants further abolish inflammasome punctum formation, caspase-1 processing and cell death. Thus, unlike other inflammasome sensors that are monomeric when inactive, our data uncover a unique NLRP3 oligomer on membrane that is poised to sense diverse signals to induce inflammasome activation.

中文翻译：

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全长 NLRP3 形成寡聚笼来介导 NLRP3 传感和激活

核苷酸结合结构域和富含亮氨酸重复序列 (LRR) 的蛋白质 3 和一个 pyrin 结构域 (NLRP3) 正在成为膜完整性的关键细胞内炎性体传感器和对抗慢性炎症的非常重要的临床靶点。在这里，我们报告全长 NLRP3 的内源性刺激响应形式是一个 12-16 mer 双环笼，通过 LRR-LRR 相互作用与组件内屏蔽的吡喃域相互作用，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，这与先前注意到的 NLRP3 在各种膜细胞器的定位一致。结构引导的诱变表明，反式高尔基网络分散到囊泡中，这是对所有 NLRP3 激活刺激物观察到的早期事件，需要 NLRP3 的双环笼。双环缺陷 NLRP3 突变体进一步消除了炎性体泪点形成、caspase-1 加工和细胞死亡。因此，与其他非活性时为单体的炎性体传感器不同，我们的数据揭示了膜上一种独特的 NLRP3 寡聚体，它准备感知各种信号以诱导炎性体激活。