title: Human cytomegalovirus glycoprotein UL16 causes intracellular sequestration of NKG2D ligands, protecting against natural killer cell cytotoxicity.
abstract: The activating receptor, NKG2D, is expressed on a variety of immune effector cells and recognizes divergent families of major histocompatibility complex (MHC) class I-related ligands, including the MIC and ULBP proteins. Infection, stress, or transformation can induce NKG2D ligand expression, resulting in effector cell activation and killing of the ligand-expressing target cell. The human cytomegalovirus (HCMV) membrane glycoprotein, UL16, binds to three of the five known ligands for human NKG2D. UL16 is retained in the endoplasmic reticulum and cis-Golgi apparatus of cells and causes MICB to be similarly retained and stabilized within cells. Coexpression of UL16 markedly reduces cell surface levels of MICB, ULBP1, and ULBP2, and decreases susceptibility to natural killer cell-mediated cytotoxicity. Domain swapping experiments demonstrate that the transmembrane and cytoplasmic domains of UL16 are important for intracellular retention of UL16, whereas the ectodomain of UL16 participates in down-regulation of NKG2D ligands. The intracellular sequestration of NKG2D ligands by UL16 represents a novel HCMV immune evasion mechanism to add to the well-documented viral strategies directed against antigen presentation by classical MHC molecules.
authors.affiliation: Department of Molecular Microbiology and Immunology, Oregon Health and Sciences University, Portland, OR 97239, USA.
authors.forename: Claire
authors.initials: C
authors.lastname: Dunn
authors.forename: N Jan
authors.initials: NJ
authors.lastname: Chalupny
authors.forename: Claire L
authors.initials: CL
authors.lastname: Sutherland
authors.forename: Stephanie
authors.initials: S
authors.lastname: Dosch
authors.forename: P V
authors.initials: PV
authors.lastname: Sivakumar
authors.forename: David C
authors.initials: DC
authors.lastname: Johnson
authors.forename: David
authors.initials: D
authors.lastname: Cosman
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001667:Binding, Competitive; D002460:Cell Line; D002462:Cell Membrane / Q000276:immunology / Q000821:virology; D003429:Cross Reactions; D003587:Cytomegalovirus / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity / Q000502:physiology; D003602:Cytotoxicity, Immunologic; D015536:Down-Regulation; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology*; D008024:Ligands; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011971:Receptors, Immunologic / Q000378:metabolism*; D055607:Receptors, Natural Killer Cell; D014764:Viral Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
chemical_list: D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; C527085:KLRK1 protein, human; C527086:Klrk1 protein, mouse; D008024:Ligands; D008562:Membrane Glycoproteins; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell; D014764:Viral Proteins