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期刊名称: Cell Research
Volume:25    Issue:12        Page:1285-1298
ISSN:1001-0602

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

作者: He Wan-Ting Wan Haoqiang Hu Lichen Chen Pengda Wang Xin
DOI:10.1038/cr.2015.139

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页码: 1285-1298
被引频次: 284
出版者: INST BIOCHEMISTRY & CELL BIOLOGY,Nature Publishing Group
期刊名称: Cell Research
ISSN: 1001-0602
卷期: Volume:25    Issue:12
语言: English
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.
相关主题: GSDMD, pyroptosis, inflammasome, apoptosis, caspase-11, IL-1β, caspase-1, PROTEIN, INFLAMMASOME ACTIVATION, IL-1 beta, CASPASE-1 AUTOPROTEOLYSIS, CELL-DEATH, CELL BIOLOGY, ASC, NECROSIS, Interleukin-1beta - secretion, Inflammasomes - metabolism, Pyroptosis, Humans, Mice, Inbred C57BL, Cells, Cultured, Neoplasm Proteins - metabolism, Apoptosis Regulatory Proteins - metabolism, Mice, Knockout, Animals, Apoptosis Regulatory Proteins - deficiency, HEK293 Cells, Apoptosis Regulatory Proteins - genetics, Mice, Neoplasm Proteins - deficiency, Neoplasm Proteins - genetics, Original,

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