Gasdermin D is an executor of pyroptosis and required for interleukin-1β secretion.
Gasdermin D is an executor of pyroptosis and required for interleukin-1β secretion.
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Gasdermin D 是焦亡的执行者，是白细胞介素 1 β 分泌所必需的
DOI：
10.1038/cr.2015.139
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发表时间：
2015-12
期刊：
影响因子：
44.1
通讯作者：
Han J
中科院分区：
文献类型：
--
作者：
He WT;Wan H;Hu L;Chen P;Wang X;Huang Z;Yang ZH;Zhong CQ;Han J
炎性小体是先天免疫系统的细胞内信号复合物。炎性小体的活化促进白细胞介素1β（IL-1β）和IL-18的分泌并触发焦亡。典型和非典型炎性体途径中的半胱天冬酶-1和-11（或人类中的-4/5）分别对于炎性体介导的炎症反应至关重要。在这里，我们报告gasdermin D（GSDMD）是炎性小体的另一个重要组成部分。我们通过基于定量质谱的分析发现了尼日利亚菌素诱导的NLRP 3炎性小体中存在GSDMD蛋白。GSDMD的基因缺失表明，GSDMD是典型和非典型炎性小体反应中的焦亡和IL-1β的分泌而非蛋白水解成熟所需的。已知GSDMD是半胱天冬酶-1的底物，并且我们显示其在炎性小体活化期间在预测位点处裂解，并且该裂解是焦亡和IL-1β分泌所需的。GSDMD的N端蛋白水解片段的表达可以触发细胞死亡，并且N端修饰如标记Flag序列破坏GSDMD的功能。我们还发现，caspase-1能够处理GSDMD和ASC不是必需的GSDMD的功能。对LPS加尼日利亚菌素或鼠伤寒沙门氏菌处理的巨噬细胞系和原代细胞的进一步分析表明，Gsdmd−/−细胞的凋亡变得明显，表明细胞凋亡受到细胞凋亡的抑制。凋亡的诱导需要NLRP 3或其他炎性体受体和ASC，而caspase-1可能部分有助于Gsdmd−/−细胞中凋亡caspase的激活。这些数据提供了新的见解，细胞凋亡和细胞凋亡之间的相互作用的分子机制，揭示了一个意想不到的。
Inflammasome is an intracellular signaling complex of the innate immune system. Activation of inflammasomes promotes the secretion of interleukin 1β (IL-1β) 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-1β 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-1β 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.