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Single-cell analysis of pyroptosis dynamics reveals conserved GSDMD-mediated subcellular events that precede plasma membrane rupture

(2019) CELL DEATH AND DIFFERENTIATION. 26(1). p.146-161
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Abstract
Pyroptosis is rapidly emerging as a mechanism of anti-microbial host defense, and of extracellular release of the inflammasome-dependent cytokines interleukin (IL)-1 beta and IL-18, which contributes to autoinflammatory pathology. Caspases 1, 4, 5 and 11 trigger this regulated form of necrosis by cleaving the pyroptosis effector gasdermin D (GSDMD), causing its pore-forming amino-terminal domain to oligomerize and perforate the plasma membrane. However, the subcellular events that precede pyroptotic cell lysis are ill defined. In this study, we triggered primary macrophages to undergo pyroptosis from three inflammasome types and recorded their dynamics and morphology using high-resolution live-cell spinning disk confocal laser microscopy. Based on quantitative analysis of single-cell subcellular events, we propose a model of pyroptotic cell disintegration that is initiated by opening of GSDMD-dependent ion channels or pores that are more restrictive than recently proposed GSDMD pores, followed by osmotic cell swelling, commitment of mitochondria and other membrane-bound organelles prior to sudden rupture of the plasma membrane and full permeability to intracellular proteins. This study provides a dynamic framework for understanding cellular changes that occur during pyroptosis, and charts a chronological sequence of GSDMD-mediated subcellular events that define pyroptotic cell death at the single-cell level.
Keywords
GASDERMIN-D, INFLAMMASOME ACTIVATION, MACROPHAGE APOPTOSIS, PORE, FORMATION, DEATH, CASPASE-11, RELEASE, BINDING, LEADS, MLKL

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Citation

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Chicago
Moraes de Vasconcelos, Nathalia, Nina Van Opdenbosch, Hanne Van Gorp, Eef Parthoens, and Mohamed Lamkanfi. 2019. “Single-cell Analysis of Pyroptosis Dynamics Reveals Conserved GSDMD-mediated Subcellular Events That Precede Plasma Membrane Rupture.” Cell Death and Differentiation 26 (1): 146–161.
APA
Moraes de Vasconcelos, N., Van Opdenbosch, N., Van Gorp, H., Parthoens, E., & Lamkanfi, M. (2019). Single-cell analysis of pyroptosis dynamics reveals conserved GSDMD-mediated subcellular events that precede plasma membrane rupture. CELL DEATH AND DIFFERENTIATION, 26(1), 146–161.
Vancouver
1.
Moraes de Vasconcelos N, Van Opdenbosch N, Van Gorp H, Parthoens E, Lamkanfi M. Single-cell analysis of pyroptosis dynamics reveals conserved GSDMD-mediated subcellular events that precede plasma membrane rupture. CELL DEATH AND DIFFERENTIATION. London: Nature Publishing Group; 2019;26(1):146–61.
MLA
Moraes de Vasconcelos, Nathalia et al. “Single-cell Analysis of Pyroptosis Dynamics Reveals Conserved GSDMD-mediated Subcellular Events That Precede Plasma Membrane Rupture.” CELL DEATH AND DIFFERENTIATION 26.1 (2019): 146–161. Print.
@article{8601017,
  abstract     = {Pyroptosis is rapidly emerging as a mechanism of anti-microbial host defense, and of extracellular release of the inflammasome-dependent cytokines interleukin (IL)-1 beta and IL-18, which contributes to autoinflammatory pathology. Caspases 1, 4, 5 and 11 trigger this regulated form of necrosis by cleaving the pyroptosis effector gasdermin D (GSDMD), causing its pore-forming amino-terminal domain to oligomerize and perforate the plasma membrane. However, the subcellular events that precede pyroptotic cell lysis are ill defined. In this study, we triggered primary macrophages to undergo pyroptosis from three inflammasome types and recorded their dynamics and morphology using high-resolution live-cell spinning disk confocal laser microscopy. Based on quantitative analysis of single-cell subcellular events, we propose a model of pyroptotic cell disintegration that is initiated by opening of GSDMD-dependent ion channels or pores that are more restrictive than recently proposed GSDMD pores, followed by osmotic cell swelling, commitment of mitochondria and other membrane-bound organelles prior to sudden rupture of the plasma membrane and full permeability to intracellular proteins. This study provides a dynamic framework for understanding cellular changes that occur during pyroptosis, and charts a chronological sequence of GSDMD-mediated subcellular events that define pyroptotic cell death at the single-cell level.},
  author       = {Moraes de Vasconcelos, Nathalia and Van Opdenbosch, Nina and Van Gorp, Hanne and Parthoens, Eef and Lamkanfi, Mohamed},
  issn         = {1350-9047},
  journal      = {CELL DEATH AND DIFFERENTIATION},
  language     = {eng},
  number       = {1},
  pages        = {146--161},
  publisher    = {Nature Publishing Group},
  title        = {Single-cell analysis of pyroptosis dynamics reveals conserved GSDMD-mediated subcellular events that precede plasma membrane rupture},
  url          = {http://dx.doi.org/10.1038/s41418-018-0106-7},
  volume       = {26},
  year         = {2019},
}

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