期刊
EMBO JOURNAL
卷 35, 期 16, 页码 1766-1778出版社
WILEY
DOI: 10.15252/embj.201694696
关键词
atomic force microscopy; cell death; gasdermin; inflammasomes; inflammation; pyroptosis
资金
- European Research Council (FP7 contract) [MOMP 281764]
- Swiss National Science Foundation [PP00P3_139120/1]
- European Union Marie Curie Actions program through the ACRITAS Initial Training Network (FP7-PEOPLE-ITN) [317348]
- Swiss National Science Foundation (SNF) [PP00P3_139120] Funding Source: Swiss National Science Foundation (SNF)
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 liposomeinserted 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.
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