Gasdermin D is an executor of pyroptosis and required for interleukin-1β secretion

被引:1881
作者
He, Wan-ting [1 ]
Wan, Haoqiang [1 ]
Hu, Lichen [1 ]
Chen, Pengda [1 ]
Wang, Xin [1 ]
Huang, Zhe [1 ]
Yang, Zhang-Hua [1 ]
Zhong, Chuan-Qi [1 ]
Han, Jiahuai [1 ]
机构
[1] Xiamen Univ, Sch Life Sci, Innovat Ctr Cell Signaling Network, State Key Lab Cellular Stress Biol, Xiamen 361005, Fujian, Peoples R China
基金
美国国家科学基金会; 中国国家自然科学基金;
关键词
GSDMD; inflammasome; pyroptosis; apoptosis; IL-1; beta; caspase-1; caspase-11; CASPASE-1; AUTOPROTEOLYSIS; INFLAMMASOME ACTIVATION; CELL-DEATH; APOPTOSIS; PROTEIN; NECROSIS; ASC;
D O I
10.1038/cr.2015.139
中图分类号
Q2 [细胞生物学];
学科分类号
071013 [干细胞生物学];
摘要
Inflammasome is an intracellular signaling complex of the innate immune system. Activation of inflammasomes promotes the secretion of interleukin 1 beta (IL-1 beta) and IL-18 and triggers pyroptosis. Caspase-1 and -11 (or -4/5 in human) in the canonical and non-canonical inflammasome pathways, respectively, are crucial for inflammasome-mediated inflammatory responses. Here we report that gasdermin D (GSDMD) is another crucial component of inflammasomes. We discovered the presence of GSDMD protein in nigericin-induced NLRP3 inflammasomes by a quantitative mass spectrometry-based analysis. Gene deletion of GSDMD demonstrated that GSDMD is required for pyroptosis and for the secretion but not proteolytic maturation of IL-1 beta in both canonical and non-canonical inflammasome responses. It was known that GSDMD is a substrate of caspase-1 and we showed its cleavage at the predicted site during inflammasome activation and that this cleavage was required for pyroptosis and IL-1 beta secretion. Expression of the N-terminal proteolytic fragment of GSDMD can trigger cell death and N-terminal modification such as tagging with Flag sequence disrupted the function of GSDMD. We also found that pro-caspase-1 is capable of processing GSDMD and ASC is not essential for GSDMD to function. Further analyses of LPS plus nigericin- or Salmonella typhimurium-treated macrophage cell lines and primary cells showed that apoptosis became apparent in Gsdmd(-/-) cells, indicating a suppression of apoptosis by pyroptosis. The induction of apoptosis required NLRP3 or other inflammasome receptors and ASC, and caspase-1 may partially contribute to the activation of apoptotic caspases in Gsdmd(-/-) cells. These data provide new insights into the molecular mechanisms of pyroptosis and reveal an unexpected interplay between apoptosis and pyroptosis.
引用
收藏
页码:1285 / 1298
页数:14
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