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

被引：2942

作者：

Kayagaki, Nobuhiko ^{[1
]}

Stowe, Irma B. ^{[1
]}

Lee, Bettina L. ^{[1
]}

O'Rourke, Karen ^{[1
]}

Anderson, Keith ^{[2
]}

Warming, Soren ^{[2
]}

Cuellar, Trinna ^{[2
]}

Haley, Benjamin ^{[2
]}

Roose-Girma, Merone ^{[2
]}

Phung, Qui T. ^{[3
]}

Liu, Peter S. ^{[3
]}

Lill, Jennie R. ^{[3
]}

Li, Hong ^{[3
]}

Wu, Jiansheng ^{[3
]}

Kummerfeld, Sarah ^{[4
]}

Zhang, Juan ^{[5
]}

Lee, Wyne P. ^{[5
]}

Snipas, Scott J. ^{[6
]}

Salvesen, Guy S. ^{[6
]}

Morris, Lucy X. ^{[7
]}

Fitzgerald, Linda ^{[7
]}

Zhang, Yafei ^{[7
]}

Bertram, Edward M. ^{[7
,8
]}

Goodnow, Christopher C. ^{[8
,9
,10
]}

Dixit, Vishva M. ^{[1
]}

机构：

[1] Genentech Inc, Dept Physiol Chem, San Francisco, CA 94080 USA

[2] Genentech Inc, Dept Mol Biol, San Francisco, CA 94080 USA

[3] Genentech Inc, Dept Prot Chem, San Francisco, CA 94080 USA

[4] Genentech Inc, Dept Bioinformat, San Francisco, CA 94080 USA

[5] Genentech Inc, Dept Immunol, San Francisco, CA 94080 USA

[6] Sanford Burnham Prebys Med Discovery Inst, Program Cell Death Signaling Networks, La Jolla, CA 92037 USA

[7] Australian Natl Univ, John Curtin Sch Med Res, Australian Phen Facil, Canberra, ACT 2601, Australia

[8] Australian Natl Univ, John Curtin Sch Med Res, Dept Immunol & Infect Dis, Canberra, ACT 2601, Australia

[9] Garvan Inst Med Res, Sydney, NSW 2010, Australia

[10] UNSW Australia, St Vincents Clin Sch, Darlinghurst, NSW 2010, Australia

来源：

NATURE | 2015年 / 526卷 / 7575期

关键词：

CELL-DEATH; ACTIVATION; INTERLEUKIN-1-BETA; PYROPTOSIS; EPITHELIUM; RECEPTORS; CRYSTALS; PROTEASE; RELEASE; MEMBERS;

D O I：

10.1038/nature15541

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Intracellular lipopolysaccharide from Gram-negative bacteria including Escherichia colt Salmonella typhimurium, Shigella flexneri, and Burkholderia thailandensis activates mouse caspase-11, causing pyroptotic cell death, interleukin-1 beta 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-1 beta 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-1 beta secretion induced by cytoplasmic lipopolysaccharide or Gram-negative bacteria. In addition, Gsdmd(-1-) 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 Grain-negative bacteria.

引用

页码：666 / 671

页数：6

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