N-glycosylation of mouse TRAIL-R restrains TRAIL-induced apoptosis.pdf (1.37 MB)
N-glycosylation of mouse TRAIL-R restrains TRAIL-induced apoptosis.
journal contributionposted on 2019-07-31, 11:44 authored by Y Estornes, Y Dondelinger, K Weber, I Bruggeman, A Peall, M MacFarlane, S Lebecque, P Vandenabeele, MJM Bertrand
The sensitivity of cells to death receptor-induced apoptosis is commonly controlled by multiple checkpoints in order to limit induction of excessive or unnecessary death. Although cytotoxic in various cancer cells, tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) does not trigger apoptosis in most non-transformed cells. The molecular nature of the checkpoints that normally protect the cells from TRAIL-induced death are not fully understood. Endoplasmic reticulum (ER) stress has been reported to switch the sensitivity of human cells to the cytotoxic effect of TRAIL, suggesting that this cellular state perturbs some of these protective mechanisms. We found that tunicamycin (TU), but no other ER stress inducers, sensitized mouse fibroblasts and hippocampal neuronal cells to TRAIL-induced apoptosis. Importantly, the sensitization was specific to TRAIL and not caused by differences in ER stress induction. Instead, it relied on the inhibition of N-glycosylation of the mouse TRAIL receptor (mTRAIL-R). Inhibition of N-glycosylation did not alter cell surface expression of mTRAIL-R but enhanced its ability to bind TRAIL, and facilitated mTRAIL-R oligomerization, which resulted in enhanced death-inducing signaling complex (DISC) formation and caspase-8 activation. Remarkably, reconstitution of mTRAIL-R-deficient cells with a version of mTRAIL-R mutated for the three N-glycosylation sites identified in its ectodomain confirmed higher sensitivity to TRAIL-induced apoptosis. Together, our results demonstrate that inhibition of N-glycosylation of mTRAIL-R, and not ER stress induction, sensitizes mouse cells to TRAIL-induced apoptosis. We therefore reveal a new mechanism restraining TRAIL cytotoxicity in mouse cells.
Research in the groups of Prof. M. Bertrand and Prof. P. Vandenabeele is supported by grants from the Vlaams Instituut voor Biotechnologie (VIB), grants from Ghent University (MRP, GROUP-ID consortium), grants from the Fonds voor Wetenschappelijk Onderzoek Vlaanderen (FWO) (G017212N, G013715N, G078713N), from the Flemish Government (Methusalem BOF09/01M00709 and BOF16/MET_V/007), and from the Belgian science policy office (BELSPO) (IAP 7/32). Dr. Dondelinger is holder of a FWO postdoctoral fellowship. Research in the group of Prof. S. Lebecque is supported by grants from the Cancéropôle Lyon Auvergne Rhône Alpes, France (PDC 016 CITCAP CLARA, Lyon) and from the Institut National de la Recherche contre le Cancer (INCA) France (PAIR CHC 2009-140).
CitationCell Death & Disease, 9 (5), pp. 494
Author affiliation/Organisation/COLLEGE OF LIFE SCIENCES/Biological Sciences/Molecular & Cell Biology
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