title: The human NKG2D ligand ULBP2 can be expressed at the cell surface with or without a GPI anchor and both forms can activate NK cells.
abstract: The activating immune receptor NKG2D binds to several stress-induced ligands that are structurally different. MHC-class-I-related chain (MIC) A/B molecules have a transmembrane domain, whereas most UL16 binding proteins (ULBPs) are glycosylphosphatidylinositol (GPI)-linked molecules. The significance of this variability in membrane anchors is unclear. Here, we demonstrate that ULBP2, but not ULBP1 or ULBP3, can reach the cell surface without the GPI modification. Several proteins are expressed at the cell surface as both transmembrane and GPI-linked molecules, either via alternative splicing or by the expression of linked genes. However, to our knowledge, ULBP2 is the first single mammalian cDNA that can be expressed as either a transmembrane or a GPI-anchored protein. The rate of maturation and the levels of cell surface expression of the non-GPI-linked form were lower than those of the GPI-linked ULBP2. Nonetheless, non-GPI ULBP2 was recognised by NKG2D and triggered NK cell cytotoxicity. These data show that differences in membrane attachment by NKG2D ligands are more important for regulation of their surface expression than for cytotoxic recognition by NKG2D and emphasise that detailed characterisation of the cell biology of individual NKG2D ligands will be necessary to allow targeted modulation of this system.
authors.affiliation: Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB21QP, UK.
authors.forename: Lola
authors.initials: L
authors.lastname: Fernández-Messina
authors.forename: Omodele
authors.initials: O
authors.lastname: Ashiru
authors.forename: Sonia
authors.initials: S
authors.lastname: Agüera-González
authors.forename: Hugh T
authors.initials: HT
authors.lastname: Reyburn
authors.forename: Mar
authors.initials: M
authors.lastname: Valés-Gómez
mesh_terms: D000818:Animals; D016466:CHO Cells; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism*; D006224:Cricetinae; D003412:Cricetulus; D003602:Cytotoxicity, Immunologic; D004721:Endoplasmic Reticulum / Q000378:metabolism; D058851:GPI-Linked Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism*; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000378:metabolism; D021381:Protein Transport
chemical_list: D058851:GPI-Linked Proteins; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D055655:NK Cell Lectin-Like Receptor Subfamily K; C423231:ULBP1 protein, human; C423230:ULBP2 protein, human; C423229:ULBP3 protein, human