1. Cryo-electron tomography of NLRP3-activated ASC complexes reveals organelle co-localization
- Author
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Yangci Liu, Haoming Zhai, Helen Alemayehu, Jérôme Boulanger, Lee J. Hopkins, Alicia C. Borgeaud, Christina Heroven, Jonathan D. Howe, Kendra E. Leigh, Clare E. Bryant, and Yorgo Modis
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Science - Abstract
Abstract NLRP3 induces caspase-1-dependent pyroptotic cell death to drive inflammation. Aberrant activity of NLRP3 occurs in many human diseases. NLRP3 activation induces ASC polymerization into a single, micron-scale perinuclear punctum. Higher resolution imaging of this signaling platform is needed to understand how it induces pyroptosis. Here, we apply correlative cryo-light microscopy and cryo-electron tomography to visualize ASC/caspase-1 in NLRP3-activated cells. The puncta are composed of branched ASC filaments, with a tubular core formed by the pyrin domain. Ribosomes and Golgi-like or endosomal vesicles permeate the filament network, consistent with roles for these organelles in NLRP3 activation. Mitochondria are not associated with ASC but have outer-membrane discontinuities the same size as gasdermin D pores, consistent with our data showing gasdermin D associates with mitochondria and contributes to mitochondrial depolarization.
- Published
- 2023
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