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

Author

Listed:
  • Yangci Liu

    (University of Cambridge, MRC Laboratory of Molecular Biology, Francis Crick Avenue
    University of Cambridge School of Clinical Medicine)

  • Haoming Zhai

    (University of Cambridge, MRC Laboratory of Molecular Biology, Francis Crick Avenue
    University of Cambridge School of Clinical Medicine)

  • Helen Alemayehu

    (University of Cambridge, MRC Laboratory of Molecular Biology, Francis Crick Avenue
    University of Cambridge School of Clinical Medicine)

  • Jérôme Boulanger

    (Francis Crick Avenue)

  • Lee J. Hopkins

    (University of Cambridge, Box 157, Level 5, Addenbrooke’s Hospital
    University of Cambridge
    Wren Therapeutics, Clarendon House)

  • Alicia C. Borgeaud

    (Francis Crick Avenue
    University of Bern)

  • Christina Heroven

    (Francis Crick Avenue
    University of Oxford)

  • Jonathan D. Howe

    (Francis Crick Avenue)

  • Kendra E. Leigh

    (University of Cambridge, MRC Laboratory of Molecular Biology, Francis Crick Avenue
    University of Cambridge School of Clinical Medicine)

  • Clare E. Bryant

    (University of Cambridge, Box 157, Level 5, Addenbrooke’s Hospital
    University of Cambridge)

  • Yorgo Modis

    (University of Cambridge, MRC Laboratory of Molecular Biology, Francis Crick Avenue
    University of Cambridge School of Clinical Medicine)

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.

Suggested Citation

  • 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 & Yorgo Modis, 2023. "Cryo-electron tomography of NLRP3-activated ASC complexes reveals organelle co-localization," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-43180-8
    DOI: 10.1038/s41467-023-43180-8
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    References listed on IDEAS

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