title: Multiple ITAM-coupled NK-cell receptors engage the Bcl10/Malt1 complex via Carma1 for NF-kappaB and MAPK activation to selectively control cytokine production.
abstract: Natural killer (NK) cells are innate immune cells that mediate resistance against viruses and tumors. They express multiple activating receptors that couple to immunoreceptor tyrosine-based activation motif (ITAM)-containing signaling chains for downstream cell activation. Ligation of activating NK-cell receptors induces NK-cell cytotoxicity and cytokine release. How these distinct events are selectively controlled is not well defined. Here we report the identification of a specific signaling pathway that operates downstream of the ITAM-coupled NK-cell receptors NK1.1, Ly49D, Ly49H, and NKG2D. Using primary NK cells from Bcl10(-/-), Malt1(-/-), Carma1(-/-), and Card9(-/-) mice, we demonstrate a key role for Bcl10 signalosomes in the activation of canonical NF-kappaB signaling as well as JNK and p38 MAPK upon NK-cell triggering. Bcl10 directly cooperates with Malt1 and depends on Carma1 (Card11) but not on Card9 for NK-cell activation. These Bcl10-dependent cascades selectively control cytokine and chemokine production but do not affect NK-cell differentiation or killing. Thus, we identify a molecular basis for the segregation of NK-cell receptor-induced signals for cytokine release and target cell killing and extend the previously recognized roles for CARD-protein/Bcl10/Malt1 complexes in ITAM receptor signaling in innate and adaptive immune cells.
authors.affiliation: III Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Olaf
authors.initials: O
authors.lastname: Gross
authors.forename: Christina
authors.initials: C
authors.lastname: Grupp
authors.forename: Christian
authors.initials: C
authors.lastname: Steinberg
authors.forename: Stephanie
authors.initials: S
authors.lastname: Zimmermann
authors.forename: Dominikus
authors.initials: D
authors.lastname: Strasser
authors.forename: Nicole
authors.initials: N
authors.lastname: Hannesschläger
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Reindl
authors.forename: Helena
authors.initials: H
authors.lastname: Jonsson
authors.forename: Hairong
authors.initials: H
authors.lastname: Huo
authors.forename: Dan R
authors.initials: DR
authors.lastname: Littman
authors.forename: Christian
authors.initials: C
authors.lastname: Peschel
authors.forename: Wayne M
authors.initials: WM
authors.lastname: Yokoyama
authors.forename: Anne
authors.initials: A
authors.lastname: Krug
authors.forename: Jürgen
authors.initials: J
authors.lastname: Ruland
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D020816:Amino Acid Motifs; D000818:Animals; D000074018:B-Cell CLL-Lymphoma 10 Protein; D053468:CARD Signaling Adaptor Proteins / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism*; D016207:Cytokines / Q000096:biosynthesis; D007694:Killer Cells, Natural; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D046912:Multiprotein Complexes; D016328:NF-kappa B / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism*; D054340:Receptors, KIR / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
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; D016207:Cytokines; D046912:Multiprotein Complexes; D016328:NF-kappa B; D009363:Neoplasm Proteins; D054340:Receptors, KIR; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020169:Caspases; C498509:Malt1 protein, mouse; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein