GSDMD membrane pore formation constitutes the mechanism of pyroptotic cell death

By Lorenzo Sborgi, S. Rühl, E. Mulvihill, J. Pipercevic, Rosalie Heilig, H. Stahlberg, C. Farady, D. Müller, Petr Brož, S. Hiller. EMBO Journal, 2016

1,060 citations recorded by the source corpus.

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.

Subfields: Molecular Biology, Public Health, Environmental and Occupational Health

View Paper: https://www.semanticscholar.org/paper/09673df457d8861945066562dfd38e33727f0994

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Molecular Biology

1. Edward A. Miao
2. S. B. Kovacs
3. M. Lamkanfi
4. F. Shao
5. Jingjin Ding
6. N. Van Opdenbosch
7. Kun Wang
8. Wenqing Gao

Citations in the corpus

• Structural Mechanism for GSDMD Targeting by Autoprocessed Caspases in Pyroptosis. (2020, background): “The cleavage removes the inhibitory GSDMD-C domain and unleashes the pore-forming GSDMD-N domain to cause membrane lysis (Aglietti et al., 2016; Ding et al., 2016; Liu et al., 2016; Sborgi et al., 2016).”
• Cleavage of DFNA5 by caspase-3 during apoptosis mediates progression to secondary necrotic/pyroptotic cell death (2017, neutral): “Full-size scans of immunoblots are shown in Supplementary Figs 12–24.”
• Gasdermins: Effectors of pyroptosis (2017, background): “The liberated PFD then integrates into the cell membrane, where an estimated 16 PFD monomers oligomerize to form a large 10–15 nm diameter pore[15,18,19]; another group suggests 21 nm[20].”