title: N-glycosylation of mouse TRAIL-R and human TRAIL-R1 enhances TRAIL-induced death.
abstract: APO2L/TRAIL (TNF-related apoptosis-inducing ligand) induces death of tumor cells through two agonist receptors, TRAIL-R1 and TRAIL-R2. We demonstrate here that N-linked glycosylation (N-glyc) plays also an important regulatory role for TRAIL-R1-mediated and mouse TRAIL receptor (mTRAIL-R)-mediated apoptosis, but not for TRAIL-R2, which is devoid of N-glycans. Cells expressing N-glyc-defective mutants of TRAIL-R1 and mouse TRAIL-R were less sensitive to TRAIL than their wild-type counterparts. Defective apoptotic signaling by N-glyc-deficient TRAIL receptors was associated with lower TRAIL receptor aggregation and reduced DISC formation, but not with reduced TRAIL-binding affinity. Our results also indicate that TRAIL receptor N-glyc impacts immune evasion strategies. The cytomegalovirus (CMV) UL141 protein, which restricts cell-surface expression of human TRAIL death receptors, binds with significant higher affinity TRAIL-R1 lacking N-glyc, suggesting that this sugar modification may have evolved as a counterstrategy to prevent receptor inhibition by UL141. Altogether our findings demonstrate that N-glyc of TRAIL-R1 promotes TRAIL signaling and restricts virus-mediated inhibition.
authors.affiliation: University Bourgogne Franche-Comté, LNC UMR866, F-21000 Dijon, France.
authors.forename: Florent
authors.initials: F
authors.lastname: Dufour
authors.affiliation: University Bourgogne Franche-Comté, LNC UMR866, F-21000 Dijon, France.
authors.forename: Thibault
authors.initials: T
authors.lastname: Rattier
authors.affiliation: University Bourgogne Franche-Comté, LNC UMR866, F-21000 Dijon, France.
authors.forename: Sarah
authors.initials: S
authors.lastname: Shirley
authors.affiliation: The La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA 92037, USA.
authors.forename: Gaelle
authors.initials: G
authors.lastname: Picarda
authors.affiliation: University Bourgogne Franche-Comté, LNC UMR866, F-21000 Dijon, France.
authors.forename: Andrei Alexandru
authors.initials: AA
authors.lastname: Constantinescu
authors.affiliation: University Bourgogne Franche-Comté, LNC UMR866, F-21000 Dijon, France.
authors.forename: Aymeric
authors.initials: A
authors.lastname: Morlé
authors.affiliation: Nanomedicine Lab, Imagery and Therapeutics, EA 4662 Univ. de Bourgogne Franche-Comté, 25030 Besançon Cedex, France.
authors.forename: Al Batoul
authors.initials: AB
authors.lastname: Zakaria
authors.affiliation: University Bourgogne Franche-Comté, LNC UMR866, F-21000 Dijon, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Marcion
authors.affiliation: University Bourgogne Franche-Comté, LNC UMR866, F-21000 Dijon, France.
authors.forename: Sebastien
authors.initials: S
authors.lastname: Causse
authors.affiliation: Apoptosis Research Centre, School of Natural Sciences, National University of Ireland, Galway, Ireland.
authors.forename: Eva
authors.initials: E
authors.lastname: Szegezdi
authors.affiliation: The La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA 92037, USA.|Department of Internal Medicine, Faculty of Medicine and Health Sciences, Ghent University, 9000 Ghent, Belgium.
authors.forename: Dirk Michael
authors.initials: DM
authors.lastname: Zajonc
authors.affiliation: University Bourgogne Franche-Comté, LNC UMR866, F-21000 Dijon, France.
authors.forename: Renaud
authors.initials: R
authors.lastname: Seigneuric
authors.affiliation: University de Bordeaux, CNRS, IPB, UMR 5248, CBMN, Institut Européen de Chimie et de Biologie, 2 rue Robert Escarpit, 33607 Pessac, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Guichard
authors.affiliation: Nanomedicine Lab, Imagery and Therapeutics, EA 4662 Univ. de Bourgogne Franche-Comté, 25030 Besançon Cedex, France.
authors.forename: Tijani
authors.initials: T
authors.lastname: Gharbi
authors.affiliation: Nanomedicine Lab, Imagery and Therapeutics, EA 4662 Univ. de Bourgogne Franche-Comté, 25030 Besançon Cedex, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Picaud
authors.affiliation: Nanomedicine Lab, Imagery and Therapeutics, EA 4662 Univ. de Bourgogne Franche-Comté, 25030 Besançon Cedex, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Herlem
authors.affiliation: University Bourgogne Franche-Comté, LNC UMR866, F-21000 Dijon, France.|Centre Georges-François Leclerc, Dijon F-21000, France.|FCS Bourgogne Franche-Comté, LipSTIC LabEx, F-21000 Dijon, France.|LNC UMR866, « Equipe labellisée Ligue contre le Cancer », F-21000 Dijon, France.
authors.forename: Carmen
authors.initials: C
authors.lastname: Garrido
authors.affiliation: Department of Biochemistry, University of Lausanne, CH-1066 Epalinges, Switzerland.
authors.forename: Pascal
authors.initials: P
authors.lastname: Schneider
authors.affiliation: The La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA 92037, USA.
authors.forename: Chris Alan
authors.initials: CA
authors.lastname: Benedict
authors.affiliation: University Bourgogne Franche-Comté, LNC UMR866, F-21000 Dijon, France.|Centre Georges-François Leclerc, Dijon F-21000, France.|FCS Bourgogne Franche-Comté, LipSTIC LabEx, F-21000 Dijon, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Micheau
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D003587:Cytomegalovirus / Q000378:metabolism; D006031:Glycosylation; D045325:HCT116 Cells; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D016297:Mutagenesis, Site-Directed; D053758:Nanoparticles / Q000737:chemistry; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016415:Sequence Alignment; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000633:toxicity*; D014415:Tunicamycin / Q000633:toxicity; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D008562:Membrane Glycoproteins; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; C583467:UL141 glycoprotein, human cytomegalovirus; D014764:Viral Proteins; D014415:Tunicamycin