N-glycosylation of mouse TRAIL-R and human TRAIL-R1 enhances TRAIL-induced death: N-glycosylation of TRAIL receptors

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.
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Cell Death and Differentiation, Nature Publishing Group, 2017, [Epub ahead of print]. 〈10.1038/cdd.2016.150〉
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Florent Dufour, Thibault Rattier, Sarah Shirley, Gaelle Picarda, Andrei Alexandru Constantinescu, et al.. N-glycosylation of mouse TRAIL-R and human TRAIL-R1 enhances TRAIL-induced death: N-glycosylation of TRAIL receptors. Cell Death and Differentiation, Nature Publishing Group, 2017, [Epub ahead of print]. 〈10.1038/cdd.2016.150〉. 〈inserm-01467849〉

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