[en] 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.
Disciplines :
Oncology
Author, co-author :
Dufour, Florent; University Bourgogne Franche-Comté, LNC UMR866, F-21000 Dijon, France.
Rattier, Thibault; University Bourgogne Franche-Comté, LNC UMR866, F-21000 Dijon, France.
Shirley, Sarah; University Bourgogne Franche-Comté, LNC UMR866, F-21000 Dijon, France.
Picarda, Gaelle; The La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla,
Constantinescu, Andrei Alexandru; University Bourgogne Franche-Comté, LNC UMR866, F-21000 Dijon, France.
Morlé, Aymeric; University Bourgogne Franche-Comté, LNC UMR866, F-21000 Dijon, France.
Zakaria, Al Batoul; Nanomedicine Lab, Imagery and Therapeutics, EA 4662 Univ. de Bourgogne
Marcion, Guillaume ; Université de Liège - ULiège > GIGA > GIGA I3 - Hematology ; University Bourgogne Franche-Comté, LNC UMR866, F-21000 Dijon, France.
Causse, Sebastien; University Bourgogne Franche-Comté, LNC UMR866, F-21000 Dijon, France.
Szegezdi, Eva; Apoptosis Research Centre, School of Natural Sciences, National University of
Zajonc, Dirk Michael; The La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, ; Department of Internal Medicine, Faculty of Medicine and Health Sciences, Ghent
Seigneuric, Renaud; University Bourgogne Franche-Comté, LNC UMR866, F-21000 Dijon, France.
Guichard, Gilles; University de Bordeaux, CNRS, IPB, UMR 5248, CBMN, Institut Européen de Chimie et
Gharbi, Tijani; Nanomedicine Lab, Imagery and Therapeutics, EA 4662 Univ. de Bourgogne
Picaud, Fabien; Nanomedicine Lab, Imagery and Therapeutics, EA 4662 Univ. de Bourgogne
Herlem, Guillaume; Nanomedicine Lab, Imagery and Therapeutics, EA 4662 Univ. de Bourgogne
Garrido, Carmen; 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.
Schneider, Pascal; Department of Biochemistry, University of Lausanne, CH-1066 Epalinges,
Benedict, Chris Alan; The La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla,
Micheau, Olivier; 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.
Bodmer JL, Schneider P, Tschopp J. The molecular architecture of the TNF superfamily. Trends Biochem Sci 2002; 27: 19-26
Gonzalvez F, Ashkenazi A. New insights into apoptosis signaling by Apo2L/TRAIL. Oncogene 2010; 29: 4752-4765
Falschlehner C, Schaefer U, Walczak H. Following TRAIL's path in the immune system. Immunology 2009; 127: 145-154
Merino D, Lalaoui N, Morizot A, Solary E, Micheau O. TRAIL in cancer therapy: present and future challenges. Expert Opin Ther Targets 2007; 11: 1299-1314
Bodmer JL, Holler N, Reynard S, Vinciguerra P, Schneider P, Juo P, et al. TRAIL receptor-2 signals apoptosis through FADD and caspase-8. Nat Cell Biol 2000; 2: 241-243
Ashkenazi A. Directing cancer cells to self-destruct with pro-apoptotic receptor agonists. Nat Rev Drug Discov 2008; 7: 1001-1012
Merino D, Lalaoui N, Morizot A, Schneider P, Solary E, Micheau O. Differential inhibition of TRAIL-mediated DR5-DISC formation by decoy receptors 1 and 2. Mol Cell Biol 2006; 26: 7046-7055
Lalaoui N, Morle A, Merino D, Jacquemin G, Iessi E, Morizot A, et al. TRAIL-R4 promotes tumor growth and resistance to apoptosis in cervical carcinoma HeLa cells through AKT. PLoS One 2011; 6: e19679
Wagner KW, Punnoose EA, Januario T, Lawrence DA, Pitti RM, Lancaster K, et al. Death-receptor O-glycosylation controls tumor-cell sensitivity to the proapoptotic ligand Apo2L/TRAIL. Nat Med 2007; 13: 1070-1077
Britt WJ. Vaccines against human cytomegalovirus: time to test. Trends Microbiol 1996; 4: 34-38
Pereira L, Maidji E, McDonagh S, Tabata T. Insights into viral transmission at the uterineplacental interface. Trends Microbiol 2005; 13: 164-174
Mohr CA, Cicin-Sain L, Wagner M, Sacher T, Schnee M, Ruzsics Z, et al. Engineering of cytomegalovirus genomes for recombinant live herpesvirus vaccines. Int J Med Microbiol 2008; 298: 115-125
Yu D, Silva MC, Shenk T. Functional map of human cytomegalovirus AD169 defined by global mutational analysis. Proc Natl Acad Sci USA 2003; 100: 12396-12401
Benedict CA. Viruses and the TNF-related cytokines, an evolving battle. Cytokine Growth Factor Rev 2003; 14: 349-357
Smith W, Tomasec P, Aicheler R, Loewendorf A, Nemcovicova I, Wang EC, et al. Human cytomegalovirus glycoprotein UL141 targets the TRAIL death receptors to thwart host innate antiviral defenses. Cell Host Microbe 2013; 13: 324-335
Verma S, Loewendorf A, Wang Q, McDonald B, Redwood A, Benedict CA. Inhibition of the TRAIL death receptor by CMV reveals its importance in NK cell-mediated antiviral defense. PLoS Pathogens 2014; 10: e1004268
Nemcovicova I, Benedict CA, Zajonc DM. Structure of human cytomegalovirus UL141 binding to TRAIL-R2 reveals novel, non-canonical death receptor interactions. PLoS Pathogens 2013; 9: e1003224
Wu GS, Burns TF, McDonald ER III, Meng RD, Kao G, Muschel R, et al. Induction of the TRAIL receptor KILLER/DR5 in p53-dependent apoptosis but not growth arrest. Oncogene 1999; 18: 6411-6418
Chauhan JS, Rao A, Raghava GP. In silico platform for prediction of N-, O-and C-glycosites in eukaryotic protein sequences. PLoS One 2013; 8: e67008
Hymowitz SG, Christinger HW, Fuh G, Ultsch M, O'Connell M, Kelley RF, et al. Triggering cell death: the crystal structure of Apo2L/TRAIL in a complex with death receptor 5. Mol Cell 1999; 4: 563-571
Shatnyeva OM, Kubarenko AV, Weber CE, Pappa A, Schwartz-Albiez R, Weber AN, et al. Modulation of the CD95-induced apoptosis: the role of CD95 N-glycosylation. PLoS One 2011; 6: e19927
Reis CR, van Der Sloot AM, Natoni A, Szegezdi E, Setroikromo R, Meijer M, et al. Rapid and efficient cancer cell killing mediated by high-affinity death receptor homotrimerizing TRAIL variants. Cell Death Dis 2010; 1: e83
Pavet V, Beyrath J, Pardin C, Morizot A, Lechner M-C, Briand J-P, et al. Multivalent DR5 peptides activate the TRAIL death pathway and exert tumoricidal activity. Cancer Res 2010; 70: 1101-1110
Jacquemin G, Granci V, Gallouet AS, Lalaoui N, Morlé A, Iessi E, et al. Quercetin-mediated Mcl-1 and survivin downregulation restores TRAIL-induced apoptosis in non-Hodgkin's lymphoma B cells. Haematologica 2012; 97: 38-46
Zakaria AB, Picaud F, Rattier T, Pudlo M, Dufour F, Saviot L, et al. Nanovectorization of TRAIL with single wall carbon nanotubes enhances tumor cell killing. Nano Lett 2015; 15: 891-895
Dufour F, Rattier T, Constentinescu AA, Zischler L, Morlé A, Ben Mabrouk H, et al. TRAIL receptor gene editing unveils TRAIL-R1 as a master player of apoptosis induced by TRAIL and ER stress. Oncotarget (in press
Takeda K, Yamaguchi N, Akiba H, Kojima Y, Hayakawa Y, Tanner JE, et al. Induction of tumor-specific T cell immunity by anti-DR5 antibody therapy. J Exp Med 2004; 199: 437-448
Shirley S, Morizot A, Micheau O. Regulating TRAIL receptor-induced cell death at the membrane: a deadly discussion. Recent Pat Anticancer Drug Discov 2011; 6: 311-323
Micheau O, Shirley S, Dufour F. Death receptors as targets in cancer. Br J Pharmacol 2013; 169: 1723-1744
MacFarlane M, Kohlhaas SL, Sutcliffe MJ, Dyer MJ, Cohen GM. TRAIL receptor-selective mutants signal to apoptosis via TRAIL-R1 in primary lymphoid malignancies. Cancer Res 2005; 65: 11265-11270
Rak JW, Basolo F, Elliott JW, Russo J, Miller FR. Cell surface glycosylation changes accompanying immortalization and transformation of normal human mammary epithelial cells. Cancer Lett 1991; 57: 27-36
Rillahan CD, Antonopoulos A, Lefort CT, Sonon R, Azadi P, Ley K, et al. Global metabolic inhibitors of sialyl-and fucosyltransferases remodel the glycome. Nat Chem Biol 2012; 8: 661-668
Liu YC, Yen HY, Chen CY, Chen CH, Cheng PF, Juan YH, et al. Sialylation and fucosylation of epidermal growth factor receptor suppress its dimerization and activation in lung cancer cells. Proc Natl Acad Sci USA 2011; 108: 11332-11337
Swindall AF, Bellis SL. Sialylation of the Fas death receptor by ST6Gal-I provides protection against Fas-mediated apoptosis in colon carcinoma cells. J Biol Chem 2011; 286: 22982-22990
Moriwaki K, Shinzaki S, Miyoshi E. GDP-mannose-4, 6-dehydratase (GMDS) deficiency renders colon cancer cells resistant to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor-and CD95-mediated apoptosis by inhibiting complex II formation. J Biol Chem 2011; 286: 43123-43133
Mazurek N, Jie Sun Y, Feng Liu K, Gilcrease MZ, Schober W, Nangia-Makker P, et al. Phosphorylated galectin-3 mediates tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) signaling by regulating PTEN in human breast carcinoma cells. J Biol Chem 2007; 282: 21337-21348
Mazurek N, Byrd JC, Sun Y, Hafley M, Ramirez K, Burks J, et al. Cell-surface galectin-3 confers resistance to TRAIL by impeding trafficking of death receptors in metastatic colon adenocarcinoma cells. Cell Death Differ 2012; 19: 523-533
Mazurek N, Byrd JC, Sun Y, Ueno S, Bresalier RS. A galectin-3 sequence polymorphism confers TRAIL sensitivity to human breast cancer cells. Cancer 2011; 117: 4375-4380
Varki A, Kannagi R, Toole BP. Glycosylation changes in cancer. In: Varki A, Cummings RD, Esko JD, Freeze HH, Stanley P, Bertozzi CR, et al. (eds). Essentials of Glycobiology, 2nd edn. Cold Spring Harbor: New York, 2009
Eude-Le Parco I, Gendronneau G, Dang T, Delacour D, Thijssen VL, Edelmann W, et al. Genetic assessment of the importance of galectin-3 in cancer initiation, progression and dissemination in mice. Glycobiology 2009; 19: 68-75
Harduin-Lepers A, Krzewinski-Recchi MA, Colomb F, Foulquier F, Groux-Degroote S, Delannoy P. Sialyltransferases functions in cancers. Front Biosci (Elite Ed) 2012; 4: 499-515
