Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling
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.
|ISBN||1476-4687 (Electronic) 0028-0836 (Linking)|
|Authors||Kayagaki, N. ; Stowe, I. B. ; Lee, B. L. ; O'Rourke, K. ; Anderson, K. ; Warming, S. ; Cuellar, T. ; Haley, B. ; Roose-Girma, M. ; Phung, Q. T. ; Liu, P. S. ; Lill, J. R. ; Li, H. ; Wu, J. ; Kummerfeld, S. ; Zhang, J. ; Lee, W. P. ; Snipas, S. J. ; Salvesen, G. S. ; Morris, L. X. ; Fitzgerald, L. ; Zhang, Y. ; Bertram, E. M. ; Goodnow, C. C. ; Dixit, V. M.;|
|Responsible Garvan Author|
|URL link to publisher's version||http://www.ncbi.nlm.nih.gov/pubmed/26375259|
|OpenAccess link to author's accepted manuscript version||https://publications.gimr.garvan.org.au/open-access/13196|