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Antagonistic nanobodies implicate mechanism of GSDMD pore formation and potential therapeutic application

Author

Listed:
  • Lisa D. J. Schiffelers

    (University of Bonn)

  • Yonas M. Tesfamariam

    (University of Bonn)

  • Lea-Marie Jenster

    (University of Bonn)

  • Stefan Diehl

    (University of Bonn)

  • Sophie C. Binder

    (University of Bonn)

  • Sabine Normann

    (University of Bonn)

  • Jonathan Mayr

    (University of Bonn)

  • Steffen Pritzl

    (University of Bonn)

  • Elena Hagelauer

    (University of Bonn)

  • Anja Kopp

    (University of Bonn
    The Walter and Eliza Hall Institute of Medical Research)

  • Assaf Alon

    (Whitehead Institute for Biomedical Research)

  • Matthias Geyer

    (University of Bonn)

  • Hidde L. Ploegh

    (Whitehead Institute for Biomedical Research)

  • Florian I. Schmidt

    (University of Bonn
    Whitehead Institute for Biomedical Research
    University of Bonn)

Abstract

Inflammasome activation results in the cleavage of gasdermin D (GSDMD) by pro-inflammatory caspases. The N-terminal domains (GSDMDNT) oligomerize and assemble pores penetrating the target membrane. As methods to study pore formation in living cells are insufficient, the order of conformational changes, oligomerization, and membrane insertion remained unclear. We have raised nanobodies (VHHs) against human GSDMD and find that cytosolic expression of VHHGSDMD-1 and VHHGSDMD-2 prevents oligomerization of GSDMDNT and pyroptosis. The nanobody-stabilized GSDMDNT monomers partition into the plasma membrane, suggesting that membrane insertion precedes oligomerization. Inhibition of GSDMD pore formation switches cell death from pyroptosis to apoptosis, likely driven by the enhanced caspase-1 activity required to activate caspase-3. Recombinant antagonistic nanobodies added to the extracellular space prevent pyroptosis and exhibit unexpected therapeutic potential. They may thus be suitable to treat the ever-growing list of diseases caused by activation of (non-) canonical inflammasomes.

Suggested Citation

  • Lisa D. J. Schiffelers & Yonas M. Tesfamariam & Lea-Marie Jenster & Stefan Diehl & Sophie C. Binder & Sabine Normann & Jonathan Mayr & Steffen Pritzl & Elena Hagelauer & Anja Kopp & Assaf Alon & Matth, 2024. "Antagonistic nanobodies implicate mechanism of GSDMD pore formation and potential therapeutic application," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-52110-1
    DOI: 10.1038/s41467-024-52110-1
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    References listed on IDEAS

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