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

N Kayagaki, IB Stowe, BL Lee, K O'Rourke… - Nature, 2015 - nature.com
N Kayagaki, IB Stowe, BL Lee, K O'Rourke, K Anderson, S Warming, T Cuellar, B Haley
Nature, 2015nature.com
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 …
Abstract
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.
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