title: Human cytomegalovirus glycoprotein UL141 targets the TRAIL death receptors to thwart host innate antiviral defenses.
abstract: Death receptors (DRs) of the TNFR superfamily contribute to antiviral immunity by promoting apoptosis and regulating immune homeostasis during infection, and viral inhibition of DR signaling can alter immune defenses. Here we identify the human cytomegalovirus (HCMV) UL141 glycoprotein as necessary and sufficient to restrict TRAIL DR function. Despite showing no primary sequence homology to TNF family cytokines, UL141 binds the ectodomains of both human TRAIL DRs with affinities comparable to the natural ligand TRAIL. UL141 binding promotes intracellular retention of the DRs, thus protecting virus infected cells from TRAIL and TRAIL-dependent NK cell-mediated killing. The identification of UL141 as a herpesvirus modulator of the TRAIL DRs strongly implicates this pathway as a regulator of host defense to HCMV and highlights UL141 as a pleiotropic inhibitor of NK cell effector function.
authors.affiliation: The La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA 92037, USA.
authors.forename: Wendell
authors.initials: W
authors.lastname: Smith
authors.forename: Peter
authors.initials: P
authors.lastname: Tomasec
authors.forename: Rebecca
authors.initials: R
authors.lastname: Aicheler
authors.forename: Andrea
authors.initials: A
authors.lastname: Loewendorf
authors.forename: Ivana
authors.initials: I
authors.lastname: Nemčovičová
authors.forename: Eddie C Y
authors.initials: EC
authors.lastname: Wang
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Stanton
authors.forename: Matt
authors.initials: M
authors.lastname: Macauley
authors.forename: Paula
authors.initials: P
authors.lastname: Norris
authors.forename: Laure
authors.initials: L
authors.lastname: Willen
authors.forename: Eva
authors.initials: E
authors.lastname: Ruckova
authors.forename: Akio
authors.initials: A
authors.lastname: Nomoto
authors.forename: Pascal
authors.initials: P
authors.lastname: Schneider
authors.forename: Gabriele
authors.initials: G
authors.lastname: Hahn
authors.forename: Dirk M
authors.initials: DM
authors.lastname: Zajonc
authors.forename: Carl F
authors.initials: CF
authors.lastname: Ware
authors.forename: Gavin W G
authors.initials: GW
authors.lastname: Wilkinson
authors.forename: Chris A
authors.initials: CA
authors.lastname: Benedict
mesh_terms: D003587:Cytomegalovirus / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D003586:Cytomegalovirus Infections / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D054884:Host-Pathogen Interactions; D006801:Humans; D007113:Immunity, Innate; D007694:Killer Cells, Natural / Q000276:immunology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D011485:Protein Binding; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D014764:Viral Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*
chemical_list: D008562:Membrane Glycoproteins; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; C505639:TNFRSF10B protein, human; C583467:UL141 glycoprotein, human cytomegalovirus; D014764:Viral Proteins