Card9 controls a non-TLR signalling pathway for innate anti-fungal immunity

Nature. 2006 Aug 10;442(7103):651-6. doi: 10.1038/nature04926. Epub 2006 Jul 12.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / deficiency
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / immunology
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Antigens, Fungal / immunology
  • B-Cell CLL-Lymphoma 10 Protein
  • CARD Signaling Adaptor Proteins
  • Candida albicans / immunology
  • Caspases / metabolism
  • Cytokines / biosynthesis
  • Cytokines / immunology
  • Fungi / immunology*
  • Immunity, Innate / immunology*
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Lectins, C-Type
  • Lymphocyte Activation / immunology
  • Membrane Proteins / metabolism
  • Mice
  • Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein
  • NF-kappa B / metabolism
  • Neoplasm Proteins / metabolism
  • Nerve Tissue Proteins / metabolism
  • Protein-Tyrosine Kinases / metabolism
  • Signal Transduction*
  • Syk Kinase
  • Toll-Like Receptors
  • Zymosan / immunology

Substances

  • Adaptor Proteins, Signal Transducing
  • Antigens, Fungal
  • B-Cell CLL-Lymphoma 10 Protein
  • Bcl10 protein, mouse
  • CARD Signaling Adaptor Proteins
  • Card9 protein, mouse
  • Cytokines
  • Intracellular Signaling Peptides and Proteins
  • Lectins, C-Type
  • Membrane Proteins
  • NF-kappa B
  • Neoplasm Proteins
  • Nerve Tissue Proteins
  • Toll-Like Receptors
  • dectin 1
  • Zymosan
  • Protein-Tyrosine Kinases
  • Syk Kinase
  • Syk protein, mouse
  • Caspases
  • Malt1 protein, mouse
  • Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein