期刊
CELL RESEARCH
卷 25, 期 12, 页码 1285-1298出版社
INST BIOCHEMISTRY & CELL BIOLOGY
DOI: 10.1038/cr.2015.139
关键词
GSDMD; inflammasome; pyroptosis; apoptosis; IL-1 beta; caspase-1; caspase-11
类别
资金
- National Basic Research Program of China (973 Program) [2015CB553800]
- National Natural Science Foundation of China [91429301, 31420103910, 31330047, 31221065]
- National Scientific and Technological Major Project [2013ZX10002-002]
- Hi-Tech Research and Development Program of China (863 program) [2012AA02A201]
- 111 Project [B12001]
- Science and Technology Foundation of Xiamen [3502Z20130027]
- National Science Foundation of China for Fostering Talents in Basic Research [J1310027]
- Open Research Fund of State Key Laboratory of Cellular Stress Biology, Xiamen University
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.
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