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

Accepted version
Peer-reviewed

Type

Article

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Authors

Liu, Yangci 
Zhai, Haoming 
Alemayehu, Helen 
Boulanger, Jérôme 
Hopkins, Lee J 

Abstract

jats:titleAbstract</jats:title>jats:pNLRP3 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.</jats:p>

Description

Keywords

Journal Title

Nature Communications

Conference Name

Journal ISSN

2041-1723
2041-1723

Volume Title

Publisher

Springer Science and Business Media LLC
Sponsorship
Wellcome Trust (101908/Z/13/Z)
Wellcome Trust (217191/Z/19/Z)
This work was supported by Senior Research Fellowships 101908/Z/13/Z and 217191/Z/19/Z from the Wellcome Trust to Y.M.; a PhD studentship from the China Scholarship Council and Cambridge Trust to Y.L.; and Investigator Award 108045/Z/15/Z from the Wellcome Trust to C.E.B.
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