Article abstract
Nature Immunology 8, 619 - 629 (2007)
Published online: 7 May 2007 | doi:10.1038/ni1466
The adaptor protein CARD9 is essential for the activation of myeloid cells through ITAM-associated and Toll-like receptors
Hiromitsu Hara1,2, Chitose Ishihara1, Arata Takeuchi1, Takayuki Imanishi1, Liquan Xue3, Stephan W Morris3, Masanori Inui4, Toshiyuki Takai4, Akira Shibuya5, Shinobu Saijo6, Yoichiro Iwakura6, Naohito Ohno7, Haruhiko Koseki8, Hiroki Yoshida2, Josef M Penninger9 & Takashi Saito1
Abstract
Immunoreceptor tyrosine-based activation motifs (ITAMs) are crucial in antigen receptor signaling in acquired immunity. Although receptors associated with the ITAM-bearing adaptors FcR
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-
B 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-B 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.
- Laboratory for Cell Signaling, RIKEN Research Center for Allergy and Immunology, Yokohama, Kanagawa 230-0045, Japan.
- Department of Biomolecular Sciences, Faculty of Medicine, Saga University, Saga, Saga 849-8501, Japan.
- Department of Pathology and Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
- Department of Experimental Immunology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Miyagi 980-8575, Japan.
- Department of Immunology, Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
- Center for Experimental Medicine, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo 108-8639, Japan.
- Laboratory for Immunopharmacology of Microbial Products, School of Pharmacy, Tokyo University of Pharmacy and Life Science, Hachioji, Tokyo 192-0392, Japan.
- Laboratory for Developmental Genetics, RIKEN Research Center for Allergy and Immunology, Yokohama, Kanagawa 230-0045, Japan.
- Institute of Molecular Biotechnology of the Austrian Academy of Sciences, 1030 Vienna, Austria.
Correspondence to: Takashi Saito1 e-mail: saito@rcai.riken.jp
Correspondence to: Hiromitsu Hara1,2 e-mail: harah@cc.saga-u.ac.jp
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