2. Academic Validation
  3. Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling

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

  • Nature. 2015 Oct 29;526(7575):666-71. doi: 10.1038/nature15541.
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

Affiliations

  • 1 Department of Physiological Chemistry, Genentech Inc., South San Francisco, California 94080, USA.
  • 2 Department of Molecular Biology, Genentech Inc., South San Francisco, California 94080, USA.
  • 3 Department of Protein Chemistry, Genentech Inc., South San Francisco, California 94080, USA.
  • 4 Department of Bioinformatics, Genentech Inc., South San Francisco, California 94080, USA.
  • 5 Department of Immunology, Genentech Inc., South San Francisco, California 94080, USA.
  • 6 Program in Cell Death Signaling Networks, Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, California 92037, USA.
  • 7 The Australian Phenomics Facility, The John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory 2601, Australia.
  • 8 Department of Immunology and Infectious Diseases, The John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory 2601, Australia.
  • 9 Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.
  • 10 St. Vincent's Clinical School, UNSW Australia, Darlinghurst, New South Wales 2010, Australia.
PMID: 26375259 DOI: 10.1038/nature15541
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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