Abstract
Apoptosis is central to the interaction between pathogenic mycobacteria and host macrophages. Caspase-8-dependent apoptosis of infected macrophages, which requires activation of the mitogen-activated protein (MAP) kinase p38, lowers the spread of mycobacteria. Here we establish a link between the release of tumor necrosis factor (TNF) and mycobacteria-mediated macrophage apoptosis. TNF activated a pathway involving the kinases ASK1, p38 and c-Abl. This pathway led to phosphorylation of FLIP(S), which facilitated its interaction with the E3 ubiquitin ligase c-Cbl. This interaction triggered proteasomal degradation of FLIP(S), which promoted activation of caspase-8 and apoptosis. Our findings identify a previously unappreciated signaling pathway needed for Mycobacterium tuberculosis-triggered macrophage cell death.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / physiology*
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CASP8 and FADD-Like Apoptosis Regulating Protein / metabolism*
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Caspase 8 / metabolism
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Cell Line
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Cell Proliferation
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Humans
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MAP Kinase Kinase Kinase 5 / genetics
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MAP Kinase Kinase Kinase 5 / metabolism
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Macrophages / microbiology
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Macrophages / physiology*
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Mice
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Mice, Knockout
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Mycobacterium tuberculosis / physiology*
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Phosphorylation
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Proteasome Endopeptidase Complex / metabolism
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Protein Binding
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Proto-Oncogene Proteins c-abl / metabolism
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Proto-Oncogene Proteins c-cbl / genetics
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Proto-Oncogene Proteins c-cbl / metabolism*
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Signal Transduction
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Tumor Necrosis Factor-alpha / metabolism*
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Ubiquitination
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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CASP8 and FADD-Like Apoptosis Regulating Protein
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Tumor Necrosis Factor-alpha
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Proto-Oncogene Proteins c-cbl
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Proto-Oncogene Proteins c-abl
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p38 Mitogen-Activated Protein Kinases
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MAP Kinase Kinase Kinase 5
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MAP3K5 protein, human
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Caspase 8
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Proteasome Endopeptidase Complex
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CBL protein, human
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Cbl protein, mouse