Sborgi, Lorenzo, Ruehl, Sebastian, Mulvihill, Estefania, Pipercevic, Joka, Heilig, Rosalie, Stahlberg, Henning, Farady, Christopher, Bueller, Daniel, Broz, Petr and Hiller, Sebastian (2016) GSDMD pore formation in the plasma membrane constitutes the mechanism of pyroptotic cell death. EMBO Journal, 35 (16). pp. 1766-1778. ISSN 1460-2075

Abstract

Pyroptosis is a type of lytic cell death initiated by inflammatory caspases. These caspases are activated within multi-protein inflammasome complexes that assemble in response to pathogens and endogenous danger signals. Pyroptotic cell death has been proposed to proceed via a plasma membrane pore, but the underlying molecular mechanism has remained unclear. Recently, Gasdermin-D (GSDMD), a member of the ill-characterized Gasdermin protein family, was identified as a caspase substrate and an essential mediator of pyroptosis. GSDMD is thus a candidate for pyroptotic pore formation. Here, we characterize GSDMD function in live cells and in vitro. We show that the N-terminal fragment of caspase-1-cleaved GSDMD rapidly targets the plasma membrane of macrophages, where it induces pore formation. In vitro, the N-terminal fragment of caspase-1-cleaved recombinant GSDMD tightly binds liposomes and forms large permeability pores. Visualization of liposome-inserted GSDMD at nm resolution by cryo-electron and atomic force microscopy shows circular pores with variable diameters of > 10 nm. Overall, these data demonstrate that GSDMD is the direct and final executor of pyroptotic cell death.

Item Type:	Article
Date Deposited:	22 Sep 2016 00:45
Last Modified:	22 Sep 2016 00:45
URI:	https://oak.novartis.com/id/eprint/29539