title: The NKG2D ligand ULBP2 is specifically regulated through an invariant chain-dependent endosomal pathway.
abstract: Soluble ULBP2 is a marker for poor prognosis in several types of cancer. In this study we demonstrate that both soluble and cell surface-bound ULBP2 is transported via a so far unrecognized endosomal pathway. ULBP2 surface expression, but not MICA/B, could specifically be targeted and retained by affecting endosomal/lysosomal integrity and protein kinase C activity. The invariant chain was further essential for endosomal transport of ULBP2. This novel pathway was identified through screening experiments by which methylselenic acid was found to possess notable NKG2D ligand regulatory properties. The protein kinase C inhibitor methylselenic acid induced MICA/B surface expression but dominantly blocked ULBP2 surface transport. Remarkably, by targeting this novel pathway we could specifically block the production of soluble ULBP2 from different, primary melanomas. Our findings strongly suggest that the endosomal transport pathway constitutes a novel therapeutic target for ULBP2-producing tumors.
authors.affiliation: Section for Experimental Animal Models, Laboratory of Immunology, Faculty of Health and Medical Sciences, University of Copenhagen, DK-1870 Frederiksberg, Denmark; and.
authors.forename: Franziska
authors.initials: F
authors.lastname: Uhlenbrock
authors.affiliation: Section for Experimental Animal Models, Laboratory of Immunology, Faculty of Health and Medical Sciences, University of Copenhagen, DK-1870 Frederiksberg, Denmark; and.
authors.forename: Michael
authors.initials: M
authors.lastname: Hagemann-Jensen
authors.affiliation: Section for Experimental Animal Models, Laboratory of Immunology, Faculty of Health and Medical Sciences, University of Copenhagen, DK-1870 Frederiksberg, Denmark; and.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Kehlet
authors.affiliation: Section for Experimental Animal Models, Laboratory of Immunology, Faculty of Health and Medical Sciences, University of Copenhagen, DK-1870 Frederiksberg, Denmark; and.
authors.forename: Lars
authors.initials: L
authors.lastname: Andresen
authors.affiliation: Department of Molecular Medicine, Institute of Virology, Slovak Academy of Sciences, 845 05 Bratislava, Slovak Republic.
authors.forename: Silvia
authors.initials: S
authors.lastname: Pastorekova
authors.affiliation: Section for Experimental Animal Models, Laboratory of Immunology, Faculty of Health and Medical Sciences, University of Copenhagen, DK-1870 Frederiksberg, Denmark; and sosk@sund.ku.dk.
authors.forename: Søren
authors.initials: S
authors.lastname: Skov
mesh_terms: D000944:Antigens, Differentiation, B-Lymphocyte / Q000235:genetics / Q000276:immunology*; D000954:Antigens, Surface / Q000096:biosynthesis / Q000276:immunology; D001692:Biological Transport / Q000187:drug effects / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002227:Carbazoles / Q000494:pharmacology; D045744:Cell Line, Tumor; D047630:Depsipeptides / Q000494:pharmacology; D011992:Endosomes / Q000276:immunology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D058851:GPI-Linked Proteins / Q000096:biosynthesis / Q000276:immunology; D057809:HEK293 Cells; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000276:immunology*; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000276:immunology; D008545:Melanoma / Q000276:immunology; D009369:Neoplasms / Q000276:immunology; D016566:Organoselenium Compounds / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000276:immunology*; D034622:RNA Interference; D012333:RNA, Messenger / Q000096:biosynthesis; D034741:RNA, Small Interfering; D014158:Transcription, Genetic / Q000187:drug effects; D000077337:Vorinostat
chemical_list: D000944:Antigens, Differentiation, B-Lymphocyte; D000954:Antigens, Surface; D002227:Carbazoles; D047630:Depsipeptides; D004791:Enzyme Inhibitors; D058851:GPI-Linked Proteins; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D036341:Intercellular Signaling Peptides and Proteins; C099187:MHC class I-related chain A; C098080:MICB antigen; D016566:Organoselenium Compounds; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C423230:ULBP2 protein, human; C045084:invariant chain; C081021:Go 6976; C012589:trichostatin A; D000077337:Vorinostat; C008493:methylselenic acid; C087123:romidepsin; D011493:Protein Kinase C