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• W111118423 abstract "The so-called X-linked inhibitor of apoptosis protein (XIAP) is the most intensively studied member of the inhibitor of apoptosis proteins (IAPs) and is the only cellular protein that directly binds to and inhibits caspases thereby blocking apoptosis. XIAP is frequently overexpressed in malignant cells and has therefore been investigated as a promising therapeutic target in cancer.Recently, IAPs have also been shown to influence pathways that modulate immune signalling via activation of NF-κB. One such pathway is the NOD signalling cascade that is responsible for the detection and defence against intracellular bacteria. XIAP has previously been shown to be an essential component of the NOD signalling cascade required for the activation of NF-κB mediated inflammatory responses.In order to study the role of XIAP in NOD signalling in response to bacterial infection, we used Shigella flexneri as a physiological stimulus for the NOD signalling cascade. Our data demonstrate that XIAP is essential for NF-κB activation after S. flexneri infection, but S. flexneri is able to efficiently down-regulate the XIAP-mediated inflammatory response.In particular, we show that S. flexneri infection co-opts the host protease calpain to cleave the BCL2 protein BID. Calpain-cleaved BID then translocates to the mitochondria where it mediates the selective release of the XIAP-antagonists SMAC and OMI from the mitochondrial intermembrane space. In the cytosol, SMAC and OMI inhibit XIAP and therefore interrupt the NOD-mediated inflammatory response. Critically, calpain-cleaved BID induces the release of SMAC and OMI, but not of Cyt c from the mitochondria. This selective permeability differentiates this process from the mitochondrial permeabilisation induced by apoptotic stimuli and permits the infected host cell not only to survive but also ensures bacterial propagation.The physiological importance of XIAP in controlling bacterial infection was confirmed in vivo in XIAP whole-body and liver-specific knockout mice, which show more bacterially induced necrotic liver lesions in response to S. flexneri infection than wildtype littermates. In contrast, SMAC/OMI and BID knockout mice, with unopposed XIAP activity, survived S. flexneri infection for much longer than wild type animals.Our findings demonstrate how the non-apoptotic antagonisation of XIAP by mitochondrial SMAC and OMI can control the delicate interaction between intracellular microbial pathogens and their hosts." @default.
• W111118423 created "2016-06-24" @default.
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• W111118423 date "2013-05-05" @default.
• W111118423 modified "2023-09-27" @default.
• W111118423 title "XIAP Confers Immunity Against Intracellular Bacteria" @default.
• W111118423 hasPublicationYear "2013" @default.
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