The adaptor protein CARD9 is essential for the activation of myeloid cells through ITAM-associated and Toll-like receptors.
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.
Hara
Hiromitsu
H
Laboratory for Cell Signaling, RIKEN Research Center for Allergy and Immunology, Yokohama, Kanagawa 230-0045, Japan. harah@cc.saga-u.ac.jp
Ishihara
Chitose
C
Takeuchi
Arata
A
Imanishi
Takayuki
T
Xue
Liquan
L
Morris
Stephan W
SW
Inui
Masanori
M
Takai
Toshiyuki
T
Shibuya
Akira
A
Saijo
Shinobu
S
Iwakura
Yoichiro
Y
Ohno
Naohito
N
Koseki
Haruhiko
H
Yoshida
Hiroki
H
Penninger
Josef M
JM
Saito
Takashi
T
D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D020816:Amino Acid Motifs; D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D053468:CARD Signaling Adaptor Proteins; D002454:Cell Differentiation; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D004789:Enzyme Activation; D006162:Guanylate Cyclase / Q000378:metabolism; D037181:Lectins, C-Type; D008088:Listeriosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D008213:Lymphocyte Activation / Q000276:immunology; D008565:Membrane Proteins / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D022423:Myeloid Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D011485:Protein Binding; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D051193:Toll-Like Receptors / Q000276:immunology / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism*; D000099181:Dectin-1
D048868:Adaptor Proteins, Signal Transducing; D053468:CARD Signaling Adaptor Proteins; D006162:Guanylate Cyclase; D037181:Lectins, C-Type; D008565:Membrane Proteins; D020928:Mitogen-Activated Protein Kinases; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D009419:Nerve Tissue Proteins; D051193:Toll-Like Receptors; D014443:Tyrosine; D000099181:Dectin-1; C513280:Card9 protein, mouse