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


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-1beta 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-1beta 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-1beta 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.

Type Journal
ISBN 1476-4687 (Electronic) 0028-0836 (Linking)
Authors Kayagaki, N.; Stowe, I. B.; Lee, B. L.; O'Rourke, K.; Anderson, K.; Warming, S.; Cuellar, T.; Haley, B.; Roose-Girma, M.; Phung, Q. T.; Liu, P. S.; Lill, J. R.; Li, H.; Wu, J.; Kummerfeld, S.; Zhang, J.; Lee, W. P.; Snipas, S. J.; Salvesen, G. S.; Morris, L. X.; Fitzgerald, L.; Zhang, Y.; Bertram, E. M.; Goodnow, C. C.; Dixit, V. M.;
Responsible Garvan Author Prof Christopher Goodnow
Publisher Name NATURE
Published Date 2015-01-01
Published Volume 526
Published Issue 7575
Published Pages 666-71
Status Published in-print
URL link to publisher's version
OpenAccess link to author's accepted manuscript version