title: A soluble fragment of the tumor antigen BCL2-associated athanogene 6 (BAG-6) is essential and sufficient for inhibition of NKp30 receptor-dependent cytotoxicity of natural killer cells.
abstract: Immunosurveillance of tumor cells depends on NKp30, a major activating receptor of human natural killer (NK) cells. The human BCL2-associated athanogene 6 (BAG-6, also known as BAT3; 1126 amino acids) is a cellular ligand of NKp30. To date, little is known about the molecular details of this receptor ligand system. Within the current study, we have located the binding site of NKp30 to a sequence stretch of 250 amino acids in the C-terminal region of BAG-6 (BAG-6(686-936)). BAG-6(686-936) forms a noncovalent dimer of 57-59 kDa, which is sufficient for high affinity interaction with NKp30 (KD < 100 nM). As our most important finding, BAG-6(686-936) inhibits NKp30-dependent signaling, interferon-γ release, and degranulation of NK cells in the presence of malignantly transformed target cells. Based on these data, we show for the first time that BAG-6(686-936) comprises a subdomain of BAG-6, which is sufficient for receptor docking and inhibition of NKp30-dependent NK cell cytotoxicity as part of a tumor immune escape mechanism. These molecular insights provide an access point to restore tumor immunosurveillance by NK cells and to increase the efficacy of cellular therapies.
authors.affiliation: From the Georg-Speyer-Haus, Institute for Biomedical Research, D-60596 Frankfurt am Main and.
authors.forename: Janina
authors.initials: J
authors.lastname: Binici
authors.forename: Jessica
authors.initials: J
authors.lastname: Hartmann
authors.forename: Julia
authors.initials: J
authors.lastname: Herrmann
authors.forename: Christine
authors.initials: C
authors.lastname: Schreiber
authors.forename: Steffen
authors.initials: S
authors.lastname: Beyer
authors.forename: Günnur
authors.initials: G
authors.lastname: Güler
authors.forename: Vitali
authors.initials: V
authors.lastname: Vogel
authors.forename: Franz
authors.initials: F
authors.lastname: Tumulka
authors.forename: Rupert
authors.initials: R
authors.lastname: Abele
authors.forename: Werner
authors.initials: W
authors.lastname: Mäntele
authors.forename: Joachim
authors.initials: J
authors.lastname: Koch
mesh_terms: D000818:Animals; D001665:Binding Sites; D015550:Cell Degranulation / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D057809:HEK293 Cells; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism*; D008024:Ligands; D051379:Mice; D018832:Molecular Chaperones / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D055628:Natural Cytotoxicity Triggering Receptor 3 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D011485:Protein Binding
chemical_list: C092009:BAG6 protein, human; D008024:Ligands; D018832:Molecular Chaperones; C431710:NCR3 protein, human; D055628:Natural Cytotoxicity Triggering Receptor 3; D007371:Interferon-gamma
keywords: BAG-6; BAT3; Immunosuppression; Innate Immunity; NKp30; Natural Killer (NK) Cell; Natural Killer Cell Receptors (NCR); Tumor Immune Escape; Tumor Immunology; Tumor Marker