Abstract
The caspase-recruitment domain-containing adaptor protein CARD9 regulates the innate signaling responses to fungal infection. Here we show that CARD9 is required for innate immune responses against intracellular pathogens. We generated Card9(-/-) mice and found that CARD9-deficient macrophages had defects in activation of the kinases p38 and Jnk but not of transcription factor NF-kappaB after bacterial and viral infection. CARD9-deficient mice failed to clear infection and showed altered cytokine production after challenge with Listeria monocytogenes. In wild-type cells, we found CARD9 inducibly associated with both the intracellular 'biosensor' Nod2 and the serine-threonine kinase RICK. Our data demonstrate that CARD9 has a critical function in Nod2-mediated activation of p38 and Jnk in innate immune responses to intracellular pathogens.
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 / immunology*
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Adaptor Proteins, Signal Transducing / metabolism*
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Animals
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CARD Signaling Adaptor Proteins
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Cells, Cultured
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Cytokines / metabolism
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Enzyme Activation
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Gene Expression
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Immunity, Innate / immunology*
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Intracellular Space / microbiology*
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Ligands
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Listeria monocytogenes / immunology*
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Listeria monocytogenes / physiology
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Macrophages / metabolism
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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NF-kappa B / metabolism
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Nod2 Signaling Adaptor Protein / metabolism
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Protein Binding
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Receptor-Interacting Protein Serine-Threonine Kinase 2 / metabolism
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Signal Transduction
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p38 Mitogen-Activated Protein Kinases / 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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Cytokines
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Ligands
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NF-kappa B
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Nod2 Signaling Adaptor Protein
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Nod2 protein, mouse
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Receptor-Interacting Protein Serine-Threonine Kinase 2
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p38 Mitogen-Activated Protein Kinases