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Nature. 2015 Oct 29;526(7575):666-71. doi: 10.1038/nature15541. Epub 2015 Sep 16.

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

Author information

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.

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.

PMID:
26375259
DOI:
10.1038/nature15541
[Indexed for MEDLINE]

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