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Caspase-11 activation requires lysis of pathogen-containing vacuoles by IFN-induced GTPases.
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.
Animals, Autophagy/immunology, Caspases/metabolism, Cytosol/microbiology, Enzyme Activation, GTP Phosphohydrolases/metabolism, Galectins/immunology, Gram-Negative Bacteria/growth & development, Gram-Negative Bacteria/immunology, Gram-Negative Bacteria/pathogenicity, Immunity, Innate/immunology, Inflammasomes/immunology, Inflammasomes/metabolism, Interferon Type I/immunology, Lipopolysaccharides/immunology, Mice, Phagosomes/immunology, Phagosomes/microbiology, Salmonella typhimurium/growth & development, Salmonella typhimurium/immunology, Vacuoles/microbiology
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