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

ABSTRACT: Inflammasome activation results in the cleavage of gasdermin D (GSDMD) by pro-inflammatory caspases. The N-terminal domains (GSDMD^NT) 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 VHH_GSDMD-1 and VHH_GSDMD-2 prevents oligomerization of GSDMD^NT and pyroptosis. The nanobody-stabilized GSDMD^NT monomers partition into the plasma membrane, suggesting that membrane insertion precedes oligomerization. Inhibition of GSDMD pore formation switches cell death from pyroptosis to ap

SUBMITTER: Schiffelers LDJ 

PROVIDER: S-EPMC11427689 | biostudies-literature | 2024 Sep

REPOSITORIES: biostudies-literature