Cryo-electron tomography of NLRP3-activated ASC complexes reveals organelle co-localization

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 ()
Additional contact information
Yangci Liu: University of Cambridge, MRC Laboratory of Molecular Biology, Francis Crick Avenue
Haoming Zhai: University of Cambridge, MRC Laboratory of Molecular Biology, Francis Crick Avenue
Helen Alemayehu: University of Cambridge, MRC Laboratory of Molecular Biology, Francis Crick Avenue
Jérôme Boulanger: Francis Crick Avenue
Lee J. Hopkins: University of Cambridge, Box 157, Level 5, Addenbrooke’s Hospital
Alicia C. Borgeaud: Francis Crick Avenue
Christina Heroven: Francis Crick Avenue
Jonathan D. Howe: Francis Crick Avenue
Kendra E. Leigh: University of Cambridge, MRC Laboratory of Molecular Biology, Francis Crick Avenue
Clare E. Bryant: University of Cambridge, Box 157, Level 5, Addenbrooke’s Hospital
Yorgo Modis: University of Cambridge, MRC Laboratory of Molecular Biology, Francis Crick Avenue

Nature Communications, 2023, vol. 14, issue 1, 1-15

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.

Date: 2023
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DOI: 10.1038/s41467-023-43180-8

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