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Sborgi, Lorenzo; Rühl, Sebastian; Mulvihill, Estefania; Pipercevic, Joka; Heilig, Rosalie; Stahlberg, Henning; Farady, Christopher J; Müller, Daniel J; Broz, Petr; Hiller, Sebastian
EMBO journal, 15 August 2016, Letnik: 35, Številka: 16Journal Article
Pyroptosis is a lytic type of cell death that is 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 the formation of 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 membrane fraction of macrophages and that it induces the formation of a plasma membrane pore. 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 nanometer resolution by cryo‐electron and atomic force microscopy shows circular pores with variable ring diameters around 20 nm. Overall, these data demonstrate that GSDMD is the direct and final executor of pyroptotic cell death. Synopsis Inflammatory caspases induce a lytic type of cell death known as pyroptosis by cleaving the protein gasdermin D. New findings show that cleaved gasdermin D targets the plasma membrane, where it forms a large permeability pore. Pyroptosis induction involves the cleavage of gasdermin D by inflammatory caspases. The N‐terminal fragment of gasdermin D targets cellular membranes and leads to plasma membrane permeabilization. Gasdermin D targets and permeabilizes liposome membranes after in vitro cleavage by caspase‐1. A caspase‐1‐processed fragment of gasdermin D inserts into plasma membranes to form large permeable pores, demonstrating the direct role of gasdermin D in pyroptotic cell death.
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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