ALBERT

Description: 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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kayagaki, Nobuhiko -- Stowe, Irma B -- Lee, Bettina L -- O'Rourke, Karen -- Anderson, Keith -- Warming, Soren -- Cuellar, Trinna -- Haley, Benjamin -- Roose-Girma, Merone -- Phung, Qui T -- Liu, Peter S -- Lill, Jennie R -- Li, Hong -- Wu, Jiansheng -- Kummerfeld, Sarah -- Zhang, Juan -- Lee, Wyne P -- Snipas, Scott J -- Salvesen, Guy S -- Morris, Lucy X -- Fitzgerald, Linda -- Zhang, Yafei -- Bertram, Edward M -- Goodnow, Christopher C -- Dixit, Vishva M -- England -- Nature. 2015 Oct 29;526(7575):666-71. doi: 10.1038/nature15541. Epub 2015 Sep 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Physiological Chemistry, Genentech Inc., South San Francisco, California 94080, USA. ; Department of Molecular Biology, Genentech Inc., South San Francisco, California 94080, USA. ; Department of Protein Chemistry, Genentech Inc., South San Francisco, California 94080, USA. ; Department of Bioinformatics, Genentech Inc., South San Francisco, California 94080, USA. ; Department of Immunology, Genentech Inc., South San Francisco, California 94080, USA. ; Program in Cell Death Signaling Networks, Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, California 92037, USA. ; The Australian Phenomics Facility, The John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory 2601, Australia. ; Department of Immunology and Infectious Diseases, The John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory 2601, Australia. ; Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia. ; St. Vincent's Clinical School, UNSW Australia, Darlinghurst, New South Wales 2010, Australia.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26375259" target="_blank"〉PubMed〈/a〉