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Nature:Gasdermin-D的先天免疫作用

摘要 : 在本期Nature上发表论文的两个小组发现,Gasdermin D (人类和小鼠中保守的、但功能未知的Gsdmd基因的产物)是炎性半胱天冬酶的一个基质。

 在本期Nature上发表论文的两个小组发现,Gasdermin D (人类和小鼠中保守的、但功能未知的Gsdmd基因的产物)是炎性半胱天冬酶的一个基质。Feng Shao及同事通过全基因组CRISPR–Cas9筛选识别出Gasdermin D是炎性半胱天冬酶的一个基质。半胱天冬酶-1和半胱天冬酶-4/5/11专门断开氨基末端Gasdermin-N域与羧基末端 Gasdermin-C域之间的连接。Vishva Dixit 及同事通过ENU诱变筛选识别出Gasdermin D是非标准炎性体通道中介导“细胞焦亡”的半胱天冬酶-11所需的基质。缺失Gasdermin D的小鼠面对致命剂量的脂多糖会受到保护。两个小组都发现,断开的N-端域足以触发“细胞焦亡”(一种形式的程序性细胞死亡)。

相关文章:Nature:北生所邵峰实验室发表细胞炎性坏死关键分子机制新研究进展

原文链接:

Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling

原文摘要:

Intracellular lipopolysaccharide from Gram-negative bacteria including Escherichia coli, Salmonella typhimurium, Shigella flexneri, and Burkholderia thailandensis activates mouse caspase-11, causing pyroptotic cell death, interleukin-1β processing, and lethal septic shock. How caspase-11 executes these downstream signalling events is largely unknown. Here we show that gasdermin D is essential for caspase-11-dependent pyroptosis and interleukin-1β maturation. A forward genetic screen with ethyl-N-nitrosourea-mutagenized mice links Gsdmd to the intracellular lipopolysaccharide response. Macrophages from Gsdmd−/− mice generated by gene targeting also exhibit defective pyroptosis and interleukin-1β secretion induced by cytoplasmic lipopolysaccharide or Gram-negative bacteria. In addition, Gsdmd−/− mice are protected from a lethal dose of lipopolysaccharide. Mechanistically, caspase-11 cleaves gasdermin D, and the resulting amino-terminal fragment promotes both pyroptosis and NLRP3-dependent activation of caspase-1 in a cell-intrinsic manner. Our data identify gasdermin D as a critical target of caspase-11 and a key mediator of the host response against Gram-negative bacteria.

来源: Nature 浏览次数:0

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