BID-dependent release of mitochondrial SMAC dampens XIAP-mediated immunity against Shigella

• Published in: The EMBO journal Vol. 33; no. 19; pp. 2171 - 2187
• Main Authors: Andree, Maria, Seeger, Jens M, Schüll, Stephan, Coutelle, Oliver, Wagner-Stippich, Diana, Wiegmann, Katja, Wunderlich, Claudia M, Brinkmann, Kerstin, Broxtermann, Pia, Witt, Axel, Fritsch, Melanie, Martinelli, Paola, Bielig, Harald, Lamkemeyer, Tobias, Rugarli, Elena I, Kaufmann, Thomas, Sterner-Kock, Anja, Wunderlich, F Thomas, Villunger, Andreas, Martins, L Miguel, Krönke, Martin, Kufer, Thomas A, Utermöhlen, Olaf, Kashkar, Hamid
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.10.2014; BlackWell Publishing Ltd
• Subjects: Animals; Apoptosis; Apoptosis Regulatory Proteins; Bacterial infections; BH3 Interacting Domain Death Agonist Protein - physiology; Blotting, Western; Carrier Proteins - metabolism; Caspases - metabolism; Cell Proliferation; Cells, Cultured; Dysentery, Bacillary - immunology; Dysentery, Bacillary - microbiology; Dysentery, Bacillary - pathology; Female; Genes; Hepatocytes - immunology; Hepatocytes - metabolism; Hepatocytes - pathology; Immune response; Immunoenzyme Techniques; inflammation; Integrases - metabolism; Male; Medical research; Membrane Potential, Mitochondrial; Mice; Mice, Inbred C57BL; Mice, Knockout; mitochondria; Mitochondria - immunology; Mitochondria - metabolism; Mitochondria - pathology; Mitochondrial Proteins - immunology; Mitochondrial Proteins - metabolism; Pathology; Proteins; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; Shigella; Shigella - immunology; Shigella - pathogenicity; Signal Transduction; SMAC; Spectrometry, Mass, Electrospray Ionization; Tandem Mass Spectrometry; X-Linked Inhibitor of Apoptosis Protein - physiology; XIAP; XIAP; SMAC; inflammation; mitochondria; Shigella
• ISSN: 0261-4189; 1460-2075
• DOI: 10.15252/embj.201387244

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. Synopsis XIAP is an essential mediator for the anti‐bacterial immune response against the Gram‐negative enteroinvasive bacterium Shigella flexneri. Shigella escapes this immune response by involving the calpain‐mediated activation of BID, which leads to the release of mitochondrial SMAC. Cytosolic SMAC antagonizes XIAP and dampens the immunity against Shigella. XIAP is a crucial component of the pro‐inflammatory response against Shigella. Shigella induces the activation of calpain, which cleaves and activates BID. Activated BID induces the release of mitochondrial SMAC in Shigella‐infected cells. Cytosolic SMAC antagonizes XIAP and dampens the anti‐bacterial inflammatory signalling. Invasive Shigella bacteria co‐opt the mitochondrial XIAP antagonist SMAC in ways that selectively decrease antibacterial inflammatory responses without triggering host cell apoptosis.