Abstract
Immunoreceptor tyrosine-based activation motifs (ITAMs) are crucial in antigen receptor signaling in acquired immunity. Although receptors associated with the ITAM-bearing adaptors FcRgamma and DAP12 on myeloid cells have been suggested to activate innate immune responses, the mechanism coupling those receptors to 'downstream' signaling events is unclear. The CARMA1-Bcl-10-MALT1 complex is critical for the activation of transcription factor NF-kappaB in lymphocytes but has an unclear function in myeloid cells. Here we report that deletion of the gene encoding the Bcl-10 adaptor-binding partner CARD9 resulted in impaired myeloid cell activation of NF-kappaB signaling by several ITAM-associated receptors. Moreover, CARD9 was required for Toll-like receptor-induced activation of dendritic cells through the activation of mitogen-activated protein kinases. Although Bcl10-/- and Card9-/- mice had similar signaling impairment in myeloid cells, Card11-/- (CARMA1-deficient) myeloid cell responses were normal, and although Card11-/- lymphocytes were defective in antigen receptor-mediated activation, Card9-/- lymphocytes were not. Thus, the activation of lymphoid and myeloid cells through ITAM-associated receptors or Toll-like receptors is regulated by CARMA1-Bcl-10 and CARD9-Bcl-10, respectively.
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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Adaptor Proteins, Signal Transducing / deficiency
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism*
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Amino Acid Motifs
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Animals
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B-Lymphocytes / cytology
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B-Lymphocytes / immunology
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B-Lymphocytes / metabolism
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CARD Signaling Adaptor Proteins
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Cell Differentiation
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Dendritic Cells / immunology
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Dendritic Cells / metabolism
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Enzyme Activation
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Guanylate Cyclase / metabolism
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Lectins, C-Type
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Listeriosis / genetics
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Listeriosis / metabolism
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Listeriosis / pathology
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Listeriosis / prevention & control
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Lymphocyte Activation / immunology
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Membrane Proteins / immunology
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Membrane Proteins / metabolism*
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Mice
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Mitogen-Activated Protein Kinases / metabolism
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Myeloid Cells / cytology
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Myeloid Cells / immunology*
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Myeloid Cells / metabolism*
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Myeloid Differentiation Factor 88 / metabolism
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NF-kappa B / metabolism
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Nerve Tissue Proteins / metabolism
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Protein Binding
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Signal Transduction
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T-Lymphocytes / cytology
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T-Lymphocytes / immunology
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T-Lymphocytes / metabolism
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Toll-Like Receptors / immunology
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Toll-Like Receptors / metabolism*
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Tyrosine / metabolism*
Substances
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Adaptor Proteins, Signal Transducing
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CARD Signaling Adaptor Proteins
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Card9 protein, mouse
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Lectins, C-Type
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Membrane Proteins
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Myeloid Differentiation Factor 88
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NF-kappa B
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Nerve Tissue Proteins
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Toll-Like Receptors
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dectin 1
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Tyrosine
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Mitogen-Activated Protein Kinases
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Guanylate Cyclase