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

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, Matthias Geyer, Hidde L. Ploegh and Florian I. Schmidt ()
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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
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

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-52110-1

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