title: Cell type-specific regulation of ITAM-mediated NF-kappaB activation by the adaptors, CARMA1 and CARD9.
abstract: Activating NK cell receptors transduce signals through ITAM-containing adaptors, including FcRgamma and DAP12. Although the caspase recruitment domain (CARD)9-Bcl10 complex is essential for FcRgamma/DAP12-mediated NF-kappaB 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-kappaB activation, whereas cytotoxicity mediated by the same receptors did not require CARMA1-Bcl10-mediated signaling. IkappaB 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-kappaB 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-kappaB activation. Thus, NF-kappaB 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.
authors.affiliation: Laboratory for Cell Signaling, RIKEN Research Center for Allergy and Immunology, Yokohama City, Kanagawa, Japan. harah@cc.saga-u.ac.jp
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Hara
authors.forename: Chitose
authors.initials: C
authors.lastname: Ishihara
authors.forename: Arata
authors.initials: A
authors.lastname: Takeuchi
authors.forename: Liquan
authors.initials: L
authors.lastname: Xue
authors.forename: Stephan W
authors.initials: SW
authors.lastname: Morris
authors.forename: Josef M
authors.initials: JM
authors.lastname: Penninger
authors.forename: Hiroki
authors.initials: H
authors.lastname: Yoshida
authors.forename: Takashi
authors.initials: T
authors.lastname: Saito
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D000074018:B-Cell CLL-Lymphoma 10 Protein; D053468:CARD Signaling Adaptor Proteins / Q000378:metabolism*; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D051550:I-kappa B Kinase / Q000276:immunology / Q000378:metabolism; D015759:Ionomycin / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism; D011971:Receptors, Immunologic / Q000276:immunology; D015398:Signal Transduction; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000074018:B-Cell CLL-Lymphoma 10 Protein; C488088:Bcl10 protein, mouse; D053468:CARD Signaling Adaptor Proteins; C496467:Card11 protein, mouse; C513280:Card9 protein, mouse; D016207:Cytokines; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D011971:Receptors, Immunologic; D015759:Ionomycin; D051550:I-kappa B Kinase; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate