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. 2015 Oct 29;526(7575):666-71.
doi: 10.1038/nature15541. Epub 2015 Sep 16.

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

Nobuhiko Kayagaki  1 , Irma B Stowe  1 , Bettina L Lee  1 , Karen O'Rourke  1 , Keith Anderson  2 , Søren Warming  2 , Trinna Cuellar  2 , Benjamin Haley  2 , Merone Roose-Girma  2 , Qui T Phung  3 , Peter S Liu  3 , Jennie R Lill  3 , Hong Li  3 , Jiansheng Wu  3 , Sarah Kummerfeld  4 , Juan Zhang  5 , Wyne P Lee  5 , Scott J Snipas  6 , Guy S Salvesen  6 , Lucy X Morris  7 , Linda Fitzgerald  7 , Yafei Zhang  7 , Edward M Bertram  7   8 , Christopher C Goodnow  8   9   10 , Vishva M Dixit  1
Affiliations

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

Nobuhiko Kayagaki et al. Nature. .

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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