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

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-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.;
Garvan Authors Prof Christopher Goodnow
Publisher Name NATURE
Published Date 2015-01-01 00:00:00
Published Volume 526
Published Issue 7575
Published Pages 666-71
URL http://www.ncbi.nlm.nih.gov/pubmed/26375259
Status Published in-print