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GSDMD pore formation in the plasma membrane constitutes the mechanism of pyroptotic cell death

Sborgi, Lorenzo and Ruehl, Sebastian and Mulvihill, Estefania and Pipercevic, Joka and Heilig, Rosalie and Stahlberg, Henning and Farady, Christopher and Bueller, Daniel and 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

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