Card9 controls a non-TLR signalling pathway for innate anti-fungal immunity.
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.
Gross
Olaf
O
III. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Ismaninger Str. 22, 81675 Munich, Germany.
Gewies
Andreas
A
Finger
Katrin
K
Schäfer
Martin
M
Sparwasser
Tim
T
Peschel
Christian
C
Förster
Irmgard
I
Ruland
Jürgen
J
D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D000946:Antigens, Fungal / Q000276:immunology; D000074018:B-Cell CLL-Lymphoma 10 Protein; D053468:CARD Signaling Adaptor Proteins; D002176:Candida albicans / Q000276:immunology; D020169:Caspases / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D005658:Fungi / Q000276:immunology*; D007113:Immunity, Innate / Q000276:immunology*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D037181:Lectins, C-Type; D008213:Lymphocyte Activation / Q000276:immunology; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D016328:NF-kappa B / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction; D000072377:Syk Kinase; D051193:Toll-Like Receptors; D015054:Zymosan / Q000276:immunology; D000099181:Dectin-1
D048868:Adaptor Proteins, Signal Transducing; D000946:Antigens, Fungal; D000074018:B-Cell CLL-Lymphoma 10 Protein; D053468:CARD Signaling Adaptor Proteins; D020169:Caspases; D016207:Cytokines; D047908:Intracellular Signaling Peptides and Proteins; D037181:Lectins, C-Type; D008565:Membrane Proteins; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D016328:NF-kappa B; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; D051193:Toll-Like Receptors; D015054:Zymosan; D000099181:Dectin-1; C488088:Bcl10 protein, mouse; C513280:Card9 protein, mouse; C000606897:Syk protein, mouse; C498509:Malt1 protein, mouse