Abstract
Immune interferon gamma (IFN-γ) is essential for mammalian host defense against intracellular pathogens. IFN-γ induces nearly 2000 host genes, yet few have any assigned function. Here, we examined a complete mouse 65-kilodalton (kD) guanylate-binding protein (Gbp) gene family as part of a 43-member IFN-γ-inducible guanosine triphosphatase (GTPase) superfamily in mouse and human genomes. Family-wide loss-of-function analysis found that at least four Gbps--Gbp1, Gbp6, Gbp7, and Gbp10--conferred cell-autonomous immunity to listerial or mycobacterial infection within macrophages and gene-deficient animals. These Gbps solicited host defense proteins, including the phagocyte oxidase, antimicrobial peptides, and autophagy effectors, to kill intracellular bacteria. Thus, specific 65-kD Gbps coordinate a potent oxidative and vesicular trafficking program to protect the host from infection.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Autophagy
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Cell Line
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GTP-Binding Proteins / chemistry
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GTP-Binding Proteins / genetics
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GTP-Binding Proteins / metabolism*
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Humans
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Immunity, Innate
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Interferon-gamma / immunology*
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Listeria monocytogenes / growth & development
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Listeria monocytogenes / immunology
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Listeria monocytogenes / pathogenicity
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Listeriosis / immunology*
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Listeriosis / metabolism
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Listeriosis / microbiology
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Lysosomes / metabolism
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Macrophages / immunology*
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Macrophages / metabolism
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Macrophages / microbiology*
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Mice
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Mycobacterium bovis / growth & development
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Mycobacterium bovis / immunology
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Mycobacterium bovis / pathogenicity
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NADPH Oxidases / metabolism
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Oxidation-Reduction
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Peptides / metabolism
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Phagocytosis
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Phagosomes / metabolism
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RNA Interference
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Tuberculosis / immunology*
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Tuberculosis / metabolism
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Tuberculosis / microbiology
Substances
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Gbp2b protein, mouse
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Peptides
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Interferon-gamma
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NADPH Oxidases
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GTP-Binding Proteins
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Gbp6 protein, mouse