title: Caspase-11 activation requires lysis of pathogen-containing vacuoles by IFN-induced GTPases.
abstract: Lipopolysaccharide from Gram-negative bacteria is sensed in the host cell cytoplasm by a non-canonical inflammasome pathway that ultimately results in caspase-11 activation and cell death. In mouse macrophages, activation of this pathway requires the production of type-I interferons, indicating that interferon-induced genes have a critical role in initiating this pathway. Here we report that a cluster of small interferon-inducible GTPases, the so-called guanylate-binding proteins, is required for the full activity of the non-canonical caspase-11 inflammasome during infections with vacuolar Gram-negative bacteria. We show that guanylate-binding proteins are recruited to intracellular bacterial pathogens and are necessary to induce the lysis of the pathogen-containing vacuole. Lysis of the vacuole releases bacteria into the cytosol, thus allowing the detection of their lipopolysaccharide by a yet unknown lipopolysaccharide sensor. Moreover, recognition of the lysed vacuole by the danger sensor galectin-8 initiates the uptake of bacteria into autophagosomes, which results in a reduction of caspase-11 activation. These results indicate that host-mediated lysis of pathogen-containing vacuoles is an essential immune function and is necessary for efficient recognition of pathogens by inflammasome complexes in the cytosol.
authors.affiliation: Focal Area Infection Biology, Biozentrum, University of Basel, CH-4056 Basel, Switzerland.
authors.forename: Etienne
authors.initials: E
authors.lastname: Meunier
authors.affiliation: 1] Focal Area Infection Biology, Biozentrum, University of Basel, CH-4056 Basel, Switzerland [2].
authors.forename: Mathias S
authors.initials: MS
authors.lastname: Dick
authors.affiliation: 1] Focal Area Infection Biology, Biozentrum, University of Basel, CH-4056 Basel, Switzerland [2].
authors.forename: Roland F
authors.initials: RF
authors.lastname: Dreier
authors.affiliation: Focal Area Infection Biology, Biozentrum, University of Basel, CH-4056 Basel, Switzerland.
authors.forename: Nura
authors.initials: N
authors.lastname: Schürmann
authors.affiliation: Department Biomedicine, University of Basel, CH-4056 Basel, Switzerland.
authors.forename: Daniela
authors.initials: D
authors.lastname: Kenzelmann Broz
authors.affiliation: Genentech Inc., South San Francisco, California 94080, USA.
authors.forename: Søren
authors.initials: S
authors.lastname: Warming
authors.affiliation: Genentech Inc., South San Francisco, California 94080, USA.
authors.forename: Merone
authors.initials: M
authors.lastname: Roose-Girma
authors.affiliation: Focal Area Infection Biology, Biozentrum, University of Basel, CH-4056 Basel, Switzerland.
authors.forename: Dirk
authors.initials: D
authors.lastname: Bumann
authors.affiliation: Genentech Inc., South San Francisco, California 94080, USA.
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Kayagaki
authors.affiliation: Department of Microbiology and Immunology, Osaka University, Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Takeda
authors.affiliation: Department of Microbiology and Immunology, Osaka University, Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Yamamoto
authors.affiliation: Focal Area Infection Biology, Biozentrum, University of Basel, CH-4056 Basel, Switzerland.
authors.forename: Petr
authors.initials: P
authors.lastname: Broz
mesh_terms: D000818:Animals; D001343:Autophagy / Q000276:immunology; D020169:Caspases / Q000378:metabolism*; D053471:Caspases, Initiator; D003600:Cytosol / Q000382:microbiology; D004789:Enzyme Activation; D020558:GTP Phosphohydrolases / Q000378:metabolism*; D037161:Galectins / Q000276:immunology; D006090:Gram-Negative Bacteria / Q000254:growth & development / Q000276:immunology* / Q000472:pathogenicity; D007113:Immunity, Innate / Q000276:immunology; D058847:Inflammasomes / Q000276:immunology / Q000378:metabolism*; D007370:Interferon Type I / Q000276:immunology*; D008070:Lipopolysaccharides / Q000276:immunology; D051379:Mice; D010588:Phagosomes / Q000276:immunology / Q000382:microbiology; D012486:Salmonella typhimurium / Q000254:growth & development / Q000276:immunology; D014617:Vacuoles / Q000382:microbiology*
chemical_list: D037161:Galectins; D058847:Inflammasomes; D007370:Interferon Type I; D008070:Lipopolysaccharides; C526554:galectin-8, mouse; C101136:Casp4 protein, mouse; D020169:Caspases; D053471:Caspases, Initiator; D020558:GTP Phosphohydrolases
references.citation: PLoS Pathog. 2013;9(6):e1003400
references.pmid: 23762026
references.citation: J Biol Chem. 2011 Sep 2;286(35):30471-30480
references.pmid: 21757726
references.citation: Science. 2013 Feb 22;339(6122):975-8
references.pmid: 23348507
references.citation: Science. 2013 Sep 13;341(6151):1246-9
references.pmid: 23887873
references.citation: Cell. 2012 Aug 3;150(3):606-19
references.pmid: 22819539
references.citation: Nature. 2004 Jul 8;430(6996):213-8
references.pmid: 15190255
references.citation: Nat Rev Immunol. 2013 Oct;13(10):722-37
references.pmid: 24064518
references.citation: Nature. 2012 Jan 15;482(7385):414-8
references.pmid: 22246324
references.citation: Cell Host Microbe. 2008 Nov 13;4(5):458-69
references.pmid: 18996346
references.citation: Proc Natl Acad Sci U S A. 2013 Jan 2;110(1):294-9
references.pmid: 23248289
references.citation: Nat Rev Immunol. 2012 Apr 25;12(5):367-82
references.pmid: 22531325
references.citation: Science. 2012 Apr 27;336(6080):481-5
references.pmid: 22461501
references.citation: Nat Med. 2013 Jul;19(7):909-15
references.pmid: 23749230
references.citation: J Exp Med. 2010 Aug 2;207(8):1745-55
references.pmid: 20603313
references.citation: PLoS Pathog. 2013 Sep;9(9):e1003538
references.pmid: 24068918
references.citation: Immunity. 2012 Aug 24;37(2):302-13
references.pmid: 22795875
references.citation: Cell Host Microbe. 2014 Jan 15;15(1):72-83
references.pmid: 24439899
references.citation: Nature. 2011 Oct 16;479(7371):117-21
references.pmid: 22002608
references.citation: Nat Med. 1998 Nov;4(11):1247-52
references.pmid: 9809547
references.citation: Proc Natl Acad Sci U S A. 2013 Jan 29;110(5):1851-6
references.pmid: 23307811
references.citation: EMBO J. 2008 Oct 8;27(19):2495-509
references.pmid: 18772884
references.citation: Science. 2013 Sep 13;341(6151):1250-3
references.pmid: 24031018
references.citation: Science. 2011 May 6;332(6030):717-21
references.pmid: 21551061
references.citation: Nature. 2012 Oct 11;490(7419):288-91
references.pmid: 22895188
references.citation: Infect Immun. 2007 Oct;75(10):4826-30
references.pmid: 17664266
references.citation: PLoS Pathog. 2013;9(6):e1003414
references.pmid: 23785284