人类 NLRP3 炎症小体激活导致微管组织中心凝结物的形成

Jue Wang, Man Wu, Venkat Magupalli, Peter Dahlberg, Hao Wu, Grant Jensen
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引用次数: 0

摘要

NLRP3 炎性体是一种介导先天性免疫炎症反应的多蛋白分子机器。它的失调与大量人类疾病有关。我们利用低温荧光引导的聚焦离子束(cryo-FIB)铣削和电子低温层析成像(cryo-ET)技术,获得了NLRP3炎症小体在不同活化阶段的原位三维图像,并达到了大分子分辨率。低温层析成像图意外地揭示了人巨噬细胞 NLRP3 炎症小体在微管组织中心(MTOC)内部和周围形成的致密凝聚体。我们还发现,激活后,跨高尔基体网络会分散,并出现 50 纳米的 NLRP3 相关囊泡,这些囊泡可能会将 NLRP3 运送到 MTOC。在激活后的较晚时间点,电子致密凝聚体逐渐凝固,细胞发生热凋亡,线粒体和自噬体结构普遍受损。
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Human NLRP3 inflammasome activation leads to formation of condensate at the microtubule organizing center
The NLRP3 inflammasome is a multi-protein molecular machine that mediates inflammatory responses in innate immunity. Its dysregulation has been linked to a large number of human diseases. Using cryogenic fluorescence-guided focused-ion-beam (cryo-FIB) milling and electron cryo-tomography (cryo-ET), we obtained 3-D images of the NLRP3 inflammasome in situ at various stages of its activation at macromolecular resolution. The cryo-tomograms unexpectedly reveal dense condensates of the human macrophage NLRP3 inflammasome that form within and around the microtubule organizing center (MTOC). We also find that following activation, the trans-Golgi network disperses and 50-nm NLRP3-associated vesicles appear which likely ferry NLRP3 to the MTOC. At later time points after activation, the electron-dense condensates progressively solidify and the cells undergo pyroptosis with widespread damaged mitochondria and autophagasomal structures.
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