Abstract
The molecular circuitry underlying innate immunity is constructed of multiple, evolutionarily conserved signaling modules with distinct regulatory targets. The MAP kinases and the IKK-NF-kappa B molecules play important roles in the initiation of immune effector responses. We have found that the Drosophila NF-kappa B protein Relish plays a crucial role in limiting the duration of JNK activation and output in response to Gram-negative infections. Relish activation is linked to proteasomal degradation of TAK1, the upstream MAP kinase kinase kinase required for JNK activation. Degradation of TAK1 leads to a rapid termination of JNK signaling, resulting in a transient JNK-dependent response that precedes the sustained induction of Relish-dependent innate immune loci. Because the IKK-NF-kappa B module also negatively regulates JNK activation in mammals, thereby controlling inflammation-induced apoptosis, the regulatory cross-talk between the JNK and NF-kappa B pathways appears to be broadly conserved.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Cell Line
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Drosophila Proteins / genetics
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Drosophila Proteins / immunology*
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Drosophila melanogaster / genetics
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Drosophila melanogaster / immunology
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Endopeptidases / metabolism
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Feedback, Physiological
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Gene Expression Regulation / immunology
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Immunity / genetics*
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JNK Mitogen-Activated Protein Kinases
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Lipopolysaccharides / pharmacology
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MAP Kinase Kinase Kinases / genetics
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MAP Kinase Kinase Kinases / immunology*
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Mitogen-Activated Protein Kinases / genetics
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Mitogen-Activated Protein Kinases / immunology*
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NF-kappa B
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Receptor Cross-Talk / immunology
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Signal Transduction / immunology
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Transcription Factors / genetics
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Transcription Factors / immunology*
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Transcription, Genetic / immunology
Substances
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Drosophila Proteins
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Lipopolysaccharides
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NF-kappa B
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Rel protein, Drosophila
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Transcription Factors
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JNK Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinases
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MAP Kinase Kinase Kinases
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MAP kinase kinase kinase 7
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Endopeptidases