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Cell Type-Specific Regulation of ITAM-Mediated NF-B Activation by the Adaptors, CARMA1 and CARD9¹

Hiromitsu Hara^2,*,, Chitose Ishihara^*, Arata Takeuchi^*, Liquan Xue, Stephan W. Morris, Josef M. Penninger, Hiroki Yoshida and Takashi Saito^2,*,¶

^* Laboratory for Cell Signaling, RIKEN Research Center for Allergy and Immunology, Yokohama City, Japan; Department of Biomolecular Sciences, Faculty of Medicine, Saga University, Saga, Japan; Department of Pathology and Oncology, St. Jude Children’s Research Hospital, Memphis, TN 38105; Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria; and ^¶ WPI Immunology Frontier Research Center, Osaka, Japan

Activating NK cell receptors transduce signals through ITAM-containing adaptors, including FcR and DAP12. Although the caspase recruitment domain (CARD)9-Bcl10 complex is essential for FcR/DAP12-mediated NF-B activation in myeloid cells, its involvement in NK cell receptor signaling is unknown. Herein we show that the deficiency of CARMA1 or Bcl10, but not CARD9, resulted in severe impairment of cytokine/chemokine production mediated by activating NK cell receptors due to a selective defect in NF-B activation, whereas cytotoxicity mediated by the same receptors did not require CARMA1-Bcl10-mediated signaling. IB kinase (IKK) activation by direct protein kinase C (PKC) stimulation with PMA plus ionomycin (P/I) was abrogated in CARMA1-deficient NK cells, similar to T and B lymphocytes, whereas CARD9-deficient dendritic cells (DCs) exhibited normal P/I-induced IKK activation. Surprisingly, CARMA1 deficiency also abrogated P/I-induced IKK activation in DCs, indicating that CARMA1 is essential for PKC-mediated NF-B activation in all cell types, although the PKC-CARMA1 axis is not used downstream of myeloid ITAM receptors. Consistently, PKC inhibition abrogated ITAM receptor-mediated activation only in NK cells but not in DCs, suggesting PKC-CARMA1-independent, CARD9-dependent ITAM receptor signaling in myeloid cells. Conversely, the overexpression of CARD9 in CARMA1-deficient cells failed to restore the PKC-mediated NF-B activation. Thus, NF-B activation signaling through ITAM receptors is regulated by a cell type-specific mechanism depending on the usage of adaptors CARMA1 and CARD9, which determines the PKC dependence of the signaling.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by a Grant-in-Aid for Research in Priority Areas from the Ministry of Education, Culture, Sports, Science and Technology of Japan; Takeda Science Foundation; National Cancer Institute Grant R01 CA87064 (to S.W.M.); Cancer Center CORE Grant CA21765; and the American Lebanese Syrian Associated Charities, St. Jude Children’s Research Hospital.

² Address correspondence and reprint requests to Dr. Takashi Saito, Laboratory for Cell Signaling, RIKEN Research Center for Allergy and Immunology, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa 230-0045, Japan. E-mail address: saito{at}rcai.riken.jp or Dr. Hiromitsu Hara, Department of Biomolecular Sciences, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga 849-8501, Japan. E-mail address: harah{at}cc.saga-u.ac.jp

³ Abbreviations used in this paper: PLC, phospholipase C; ADCC, Ab-dependent cell cytotoxicity; BM, bone marrow; BMDC, bone marrow-derived dendritic cell; CARD, caspase recruitment domain; CBM, CARMA1-Bcl10-MALT1; DC, dendritic cell; IKK, IB kinase; LAMP, lysosomal-associated membrane protein; L-CBM, lymphoid-type CARMA1-Bcl10-MALT1; M-CBM, myeloid-type CARD9-Bcl10-MALT1; P/I, PMA plus ionomycin; PKC, protein kinase C; WT, wild type.

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