Abstract
The C-type lectin dectin-1 activates the transcription factor NF-kappaB through a Syk kinase-dependent signaling pathway to induce antifungal immunity. Here we show that dectin-1 expressed on human dendritic cells activates not only the Syk-dependent canonical NF-kappaB subunits p65 and c-Rel, but also the noncanonical NF-kappaB subunit RelB. Dectin-1, when stimulated by the beta-glucan curdlan or by Candida albicans, induced a second signaling pathway mediated by the serine-threonine kinase Raf-1, which integrated with the Syk pathway at the point of NF-kappaB activation. Raf-1 antagonized Syk-induced RelB activation by promoting sequestration of RelB into inactive p65-RelB dimers, thereby altering T helper cell differentiation. Thus, dectin-1 activates two independent signaling pathways, one through Syk and one through Raf-1, to induce immune responses.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylation
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Candida albicans / immunology
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Cell Differentiation / immunology*
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Cytokines / biosynthesis
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Cytokines / immunology
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Enzyme Activation / immunology*
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Enzyme-Linked Immunosorbent Assay
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Gene Expression Regulation / immunology
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Humans
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Immunoprecipitation
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Intracellular Signaling Peptides and Proteins / immunology
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Intracellular Signaling Peptides and Proteins / metabolism
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Lectins, C-Type
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Membrane Proteins / immunology
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Membrane Proteins / metabolism*
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Mycoses / immunology
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NF-kappa B / immunology
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NF-kappa B / metabolism*
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Nerve Tissue Proteins / immunology
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Nerve Tissue Proteins / metabolism*
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Phosphorylation
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Protein-Tyrosine Kinases / immunology
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Protein-Tyrosine Kinases / metabolism
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Proto-Oncogene Proteins c-raf / immunology
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Proto-Oncogene Proteins c-raf / metabolism
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RNA Interference
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction / immunology*
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Syk Kinase
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T-Lymphocytes, Helper-Inducer / cytology*
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T-Lymphocytes, Helper-Inducer / immunology
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T-Lymphocytes, Helper-Inducer / metabolism
Substances
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Cytokines
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Intracellular Signaling Peptides and Proteins
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Lectins, C-Type
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Membrane Proteins
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NF-kappa B
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Nerve Tissue Proteins
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dectin 1
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Protein-Tyrosine Kinases
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SYK protein, human
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Syk Kinase
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Proto-Oncogene Proteins c-raf