Abstract
Fungal infections are increasing worldwide due to the marked rise in immunodeficiencies including AIDS; however, immune responses to fungi are poorly understood. Dectin-1 is the major mammalian pattern recognition receptor for the fungal component zymosan. Dectin-1 represents the prototype of innate non-Toll-like receptors (TLRs) containing immunoreceptor tyrosine-based activation motifs (ITAMs) related to those of adaptive antigen receptors. Here we identify Card9 as a key transducer of Dectin-1 signalling. Although being dispensable for TLR/MyD88-induced responses, Card9 controls Dectin-1-mediated myeloid cell activation, cytokine production and innate anti-fungal immunity. Card9 couples to Bcl10 and regulates Bcl10-Malt1-mediated NF-kappaB activation induced by zymosan. Yet, Card9 is dispensable for antigen receptor signalling that uses Carma1 as a link to Bcl10-Malt1. Thus, our results define a novel innate immune pathway and indicate that evolutionarily distinct ITAM receptors in innate and adaptive immune cells use diverse adaptor proteins to engage selectively the conserved Bcl10-Malt1 module.
Publication types
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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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Antigens, Fungal / immunology
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B-Cell CLL-Lymphoma 10 Protein
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CARD Signaling Adaptor Proteins
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Candida albicans / immunology
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Caspases / metabolism
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Cytokines / biosynthesis
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Cytokines / immunology
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Fungi / immunology*
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Immunity, Innate / immunology*
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Intracellular Signaling Peptides and Proteins / metabolism
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Lectins, C-Type
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Lymphocyte Activation / immunology
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Membrane Proteins / metabolism
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Mice
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Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein
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NF-kappa B / metabolism
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Neoplasm Proteins / metabolism
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Nerve Tissue Proteins / metabolism
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Protein-Tyrosine Kinases / metabolism
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Signal Transduction*
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Syk Kinase
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Toll-Like Receptors
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Zymosan / immunology
Substances
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Adaptor Proteins, Signal Transducing
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Antigens, Fungal
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B-Cell CLL-Lymphoma 10 Protein
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Bcl10 protein, mouse
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CARD Signaling Adaptor Proteins
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Card9 protein, mouse
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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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Neoplasm Proteins
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Nerve Tissue Proteins
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Toll-Like Receptors
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dectin 1
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Zymosan
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Protein-Tyrosine Kinases
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Syk Kinase
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Syk protein, mouse
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Caspases
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Malt1 protein, mouse
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Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein