Details

Autor(en) / Beteiligte

• Kayagaki, Nobuhiko
• Stowe, Irma B.
• Lee, Bettina L.
• O’Rourke, Karen
• Anderson, Keith
• Warming, Søren
• Cuellar, Trinna
• Haley, Benjamin
• Roose-Girma, Merone
• Phung, Qui T.
• Liu, Peter S.
• Lill, Jennie R.
• Li, Hong
• Wu, Jiansheng
• Kummerfeld, Sarah
• Zhang, Juan
• Lee, Wyne P.
• Snipas, Scott J.
• Salvesen, Guy S.
• Morris, Lucy X.
• Fitzgerald, Linda
• Zhang, Yafei
• Bertram, Edward M.
• Goodnow, Christopher C.
• Dixit, Vishva M.

Titel

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

Ist Teil von

• Nature (London), 2015-10, Vol.526 (7575), p.666-671

Ort / Verlag

London: Nature Publishing Group UK

Erscheinungsjahr

2015

Quelle

EBSCOhost Psychology and Behavioral Sciences Collection

Beschreibungen/Notizen

• 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. Gasdermin D is identified as the required substrate for pyroptosis, mediating caspase-11 function in the non-canonical inflammasome pathway; the cleaved N-terminal domain is shown to trigger pyroptosis.