title: Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling.
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.
authors.affiliation: Department of Physiological Chemistry, Genentech Inc., South San Francisco, California 94080, USA.
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Kayagaki
authors.affiliation: Department of Physiological Chemistry, Genentech Inc., South San Francisco, California 94080, USA.
authors.forename: Irma B
authors.initials: IB
authors.lastname: Stowe
authors.affiliation: Department of Physiological Chemistry, Genentech Inc., South San Francisco, California 94080, USA.
authors.forename: Bettina L
authors.initials: BL
authors.lastname: Lee
authors.affiliation: Department of Physiological Chemistry, Genentech Inc., South San Francisco, California 94080, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: O'Rourke
authors.affiliation: Department of Molecular Biology, Genentech Inc., South San Francisco, California 94080, USA.
authors.forename: Keith
authors.initials: K
authors.lastname: Anderson
authors.affiliation: Department of Molecular Biology, Genentech Inc., South San Francisco, California 94080, USA.
authors.forename: Søren
authors.initials: S
authors.lastname: Warming
authors.affiliation: Department of Molecular Biology, Genentech Inc., South San Francisco, California 94080, USA.
authors.forename: Trinna
authors.initials: T
authors.lastname: Cuellar
authors.affiliation: Department of Molecular Biology, Genentech Inc., South San Francisco, California 94080, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Haley
authors.affiliation: Department of Molecular Biology, Genentech Inc., South San Francisco, California 94080, USA.
authors.forename: Merone
authors.initials: M
authors.lastname: Roose-Girma
authors.affiliation: Department of Protein Chemistry, Genentech Inc., South San Francisco, California 94080, USA.
authors.forename: Qui T
authors.initials: QT
authors.lastname: Phung
authors.affiliation: Department of Protein Chemistry, Genentech Inc., South San Francisco, California 94080, USA.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Liu
authors.affiliation: Department of Protein Chemistry, Genentech Inc., South San Francisco, California 94080, USA.
authors.forename: Jennie R
authors.initials: JR
authors.lastname: Lill
authors.affiliation: Department of Protein Chemistry, Genentech Inc., South San Francisco, California 94080, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Protein Chemistry, Genentech Inc., South San Francisco, California 94080, USA.
authors.forename: Jiansheng
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Bioinformatics, Genentech Inc., South San Francisco, California 94080, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Kummerfeld
authors.affiliation: Department of Immunology, Genentech Inc., South San Francisco, California 94080, USA.
authors.forename: Juan
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Immunology, Genentech Inc., South San Francisco, California 94080, USA.
authors.forename: Wyne P
authors.initials: WP
authors.lastname: Lee
authors.affiliation: Program in Cell Death Signaling Networks, Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, California 92037, USA.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Snipas
authors.affiliation: Program in Cell Death Signaling Networks, Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, California 92037, USA.
authors.forename: Guy S
authors.initials: GS
authors.lastname: Salvesen
authors.affiliation: The Australian Phenomics Facility, The John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory 2601, Australia.
authors.forename: Lucy X
authors.initials: LX
authors.lastname: Morris
authors.affiliation: The Australian Phenomics Facility, The John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory 2601, Australia.
authors.forename: Linda
authors.initials: L
authors.lastname: Fitzgerald
authors.affiliation: The Australian Phenomics Facility, The John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory 2601, Australia.
authors.forename: Yafei
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Edward M
authors.initials: EM
authors.lastname: Bertram
authors.affiliation: 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.
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Goodnow
authors.affiliation: Department of Physiological Chemistry, Genentech Inc., South San Francisco, California 94080, USA.
authors.forename: Vishva M
authors.initials: VM
authors.lastname: Dixit
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism*; D053471:Caspases, Initiator; D002460:Cell Line; D005260:Female; D006090:Gram-Negative Bacteria / Q000276:immunology; D006801:Humans; D058847:Inflammasomes / Q000187:drug effects / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D009154:Mutation / Q000235:genetics; D009336:Necrosis; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D028044:Phosphate-Binding Proteins; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D018805:Sepsis / Q000382:microbiology; D015398:Signal Transduction / Q000235:genetics; D016019:Survival Analysis; D000094524:Gasdermins
chemical_list: D051017:Apoptosis Regulatory Proteins; D020169:Caspases; D053471:Caspases, Initiator; D058847:Inflammasomes; D053583:Interleukin-1beta; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D009363:Neoplasm Proteins; D028044:Phosphate-Binding Proteins; C498366:GSDMD protein, human; D000094524:Gasdermins; C498368:Gsdmd protein, mouse; C101136:Casp4 protein, mouse