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

Nobuhiko Kayagaki (), Irma B. Stowe, Bettina L. Lee, Karen O’Rourke, Keith Anderson, Søren Warming, Trinna Cuellar, Benjamin Haley, Merone Roose-Girma, Qui T. Phung, Peter S. Liu, Jennie R. Lill, Hong Li, Jiansheng Wu, Sarah Kummerfeld, Juan Zhang, Wyne P. Lee, Scott J. Snipas, Guy S. Salvesen, Lucy X. Morris, Linda Fitzgerald, Yafei Zhang, Edward M. Bertram, Christopher C. Goodnow and Vishva M. Dixit ()
Additional contact information
Nobuhiko Kayagaki: Genentech Inc.
Irma B. Stowe: Genentech Inc.
Bettina L. Lee: Genentech Inc.
Karen O’Rourke: Genentech Inc.
Keith Anderson: Genentech Inc.
Søren Warming: Genentech Inc.
Trinna Cuellar: Genentech Inc.
Benjamin Haley: Genentech Inc.
Merone Roose-Girma: Genentech Inc.
Qui T. Phung: Genentech Inc.
Peter S. Liu: Genentech Inc.
Jennie R. Lill: Genentech Inc.
Hong Li: Genentech Inc.
Jiansheng Wu: Genentech Inc.
Sarah Kummerfeld: Genentech Inc.
Juan Zhang: Genentech Inc.
Wyne P. Lee: Genentech Inc.
Scott J. Snipas: Program in Cell Death Signaling Networks, Sanford-Burnham-Prebys Medical Discovery Institute
Guy S. Salvesen: Program in Cell Death Signaling Networks, Sanford-Burnham-Prebys Medical Discovery Institute
Lucy X. Morris: The Australian Phenomics Facility, The John Curtin School of Medical Research, The Australian National University
Linda Fitzgerald: The Australian Phenomics Facility, The John Curtin School of Medical Research, The Australian National University
Yafei Zhang: The Australian Phenomics Facility, The John Curtin School of Medical Research, The Australian National University
Edward M. Bertram: The Australian Phenomics Facility, The John Curtin School of Medical Research, The Australian National University
Christopher C. Goodnow: The John Curtin School of Medical Research, The Australian National University
Vishva M. Dixit: Genentech Inc.

Nature, 2015, vol. 526, issue 7575, 666-671

Abstract: 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.

Date: 2015
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DOI: 10.1038/nature15541

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