Single-cell analysis of pyroptosis dynamics reveals conserved GSDMD-mediated subcellular events that precede plasma membrane rupture.
Single-cell analysis of pyroptosis dynamics reveals conserved GSDMD-mediated subcellular events that precede plasma membrane rupture.
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DOI：
10.1038/s41418-018-0106-7
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发表时间：
2019-01
影响因子：
12.4
通讯作者：
Lamkanfi M
中科院分区：
文献类型：
--
作者：
de Vasconcelos NM;Van Opdenbosch N;Van Gorp H;Parthoens E;Lamkanfi M
焦亡作为抗微生物宿主防御的机制以及炎性体依赖性细胞因子白细胞介素（IL）-1β和IL-18的细胞外释放的机制迅速出现，这有助于自身炎性病理学。半胱天冬酶1、4、5和11通过裂解焦亡效应因子gasdermin D（GSDMD），导致其成孔氨基末端结构域寡聚化并使质膜变性来触发这种受调节形式的坏死。然而，亚细胞的事件之前，pyroptotic细胞溶解不明确。在这项研究中，我们触发了三种炎性小体类型的原代巨噬细胞发生焦亡，并使用高分辨率活细胞旋转圆盘共聚焦激光显微镜记录了它们的动力学和形态。基于单细胞亚细胞事件的定量分析，我们提出了一个模型的pyroptotic细胞解体，是由开放的GSDMD依赖的离子通道或孔，比最近提出的GSDMD孔更限制性，随后渗透性细胞肿胀，承诺的线粒体和其他膜结合的细胞器之前，质膜和细胞内蛋白质的完全渗透性突然破裂。这项研究提供了一个动态的框架，了解细胞的变化，发生在pyroptosis，并图表的时间顺序GSDMD介导的亚细胞事件，定义pyroptotic细胞死亡在单细胞水平。
Pyroptosis is rapidly emerging as a mechanism of anti-microbial host defense, and of extracellular release of the inflammasome-dependent cytokines interleukin (IL)-1β 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.
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影响因子：
4.5
作者：
Li Z;Venegas V;Nagaoka Y;Morino E;Raghavan P;Audhya A;Nakanishi Y;Zhou Z
通讯作者：
Zhou Z
DOI：
10.1073/pnas.1607769113
发表时间：
2016-07-12
影响因子：
11.1
作者：
Aglietti, Robin A.;Estevez, Alberto;Dueber, Erin C.
通讯作者：
Dueber, Erin C.
影响因子：
3.6
作者：
Brennan, MA;Cookson, BT
通讯作者：
Cookson, BT
影响因子：
12.4
作者：
Martín-Sánchez F;Diamond C;Zeitler M;Gomez AI;Baroja-Mazo A;Bagnall J;Spiller D;White M;Daniels MJ;Mortellaro A;Peñalver M;Paszek P;Steringer JP;Nickel W;Brough D;Pelegrín P
通讯作者：
Pelegrín P
影响因子：
64.8
作者：
Ding, Jingjin;Wang, Kun;Shao, Feng
通讯作者：
Shao, Feng