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
  • 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.