title: BID-dependent release of mitochondrial SMAC dampens XIAP-mediated immunity against Shigella.
abstract: The X-linked inhibitor of apoptosis protein (XIAP) is a potent caspase inhibitor, best known for its anti-apoptotic function in cancer. During apoptosis, XIAP is antagonized by SMAC, which is released from the mitochondria upon caspase-mediated activation of BID. Recent studies suggest that XIAP is involved in immune signaling. Here, we explore XIAP as an important mediator of an immune response against the enteroinvasive bacterium Shigella flexneri, both in vitro and in vivo. Our data demonstrate for the first time that Shigella evades the XIAP-mediated immune response by inducing the BID-dependent release of SMAC from the mitochondria. Unlike apoptotic stimuli, Shigella activates the calpain-dependent cleavage of BID to trigger the release of SMAC, which antagonizes the inflammatory action of XIAP without inducing apoptosis. Our results demonstrate how the cellular death machinery can be subverted by an invasive pathogen to ensure bacterial colonization.
authors: Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, Cologne, Germany Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
authors: Maria
authors: M
authors: Andree
authors: Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, Cologne, Germany Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
authors: Jens M
authors: JM
authors: Seeger
authors: Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, Cologne, Germany Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
authors: Stephan
authors: S
authors: Schüll
authors: Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, Cologne, Germany Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
authors: Oliver
authors: O
authors: Coutelle
authors: Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, Cologne, Germany Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
authors: Diana
authors: D
authors: Wagner-Stippich
authors: Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, Cologne, Germany.
authors: Katja
authors: K
authors: Wiegmann
authors: Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany Max Planck Institute for Metabolism Research, Cologne, Germany.
authors: Claudia M
authors: CM
authors: Wunderlich
authors: Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, Cologne, Germany Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
authors: Kerstin
authors: K
authors: Brinkmann
authors: Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, Cologne, Germany Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
authors: Pia
authors: P
authors: Broxtermann
authors: Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, Cologne, Germany Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
authors: Axel
authors: A
authors: Witt
authors: Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, Cologne, Germany Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
authors: Melanie
authors: M
authors: Fritsch
authors: Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany Max Planck Institute for Metabolism Research, Cologne, Germany.
authors: Paola
authors: P
authors: Martinelli
authors: Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, Cologne, Germany.
authors: Harald
authors: H
authors: Bielig
authors: Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
authors: Tobias
authors: T
authors: Lamkemeyer
authors: Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany Max Planck Institute for Metabolism Research, Cologne, Germany.
authors: Elena I
authors: EI
authors: Rugarli
authors: Institute of Pharmacology, University of Bern, Bern, Switzerland.
authors: Thomas
authors: T
authors: Kaufmann
authors: Center for Experimental Medicine (CEM), University of Cologne, Cologne, Germany.
authors: Anja
authors: A
authors: Sterner-Kock
authors: Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany Max Planck Institute for Metabolism Research, Cologne, Germany.
authors: F Thomas
authors: FT
authors: Wunderlich
authors: Division of Developmental Immunology, Biocenter, Innsbruck Medical University, Innsbruck, Austria.
authors: Andreas
authors: A
authors: Villunger
authors: Cell Death Regulation Laboratory, MRC Toxicology Unit, Leicester, UK.
authors: L Miguel
authors: LM
authors: Martins
authors: Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, Cologne, Germany Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
authors: Martin
authors: M
authors: Krönke
authors: Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, Cologne, Germany.
authors: Thomas A
authors: TA
authors: Kufer
authors: Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, Cologne, Germany Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
authors: Olaf
authors: O
authors: Utermöhlen
authors: Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, Cologne, Germany Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany h.kashkar@uni-koeln.de.
authors: Hamid
authors: H
authors: Kashkar
mesh_terms: D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D051023:BH3 Interacting Domain Death Agonist Protein / Q000502:physiology*; D015153:Blotting, Western; D002352:Carrier Proteins / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D004405:Dysentery, Bacillary / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D005260:Female; D022781:Hepatocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D007124:Immunoenzyme Techniques; D019426:Integrases / Q000378:metabolism; D008297:Male; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D024101:Mitochondrial Proteins / Q000276:immunology / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012760:Shigella / Q000276:immunology* / Q000472:pathogenicity; D015398:Signal Transduction; D021241:Spectrometry, Mass, Electrospray Ionization; D053719:Tandem Mass Spectrometry; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000502:physiology*
chemical_list: D051017:Apoptosis Regulatory Proteins; D051023:BH3 Interacting Domain Death Agonist Protein; C494815:Bid protein, mouse; D002352:Carrier Proteins; C499605:Diablo protein, mouse; D024101:Mitochondrial Proteins; D012333:RNA, Messenger; D051636:X-Linked Inhibitor of Apoptosis Protein; C045073:Cre recombinase; D019426:Integrases; D020169:Caspases
keywords: SMAC; Shigella; XIAP; inflammation; mitochondria