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N-glycosylation of mouse TRAIL-R restrains TRAIL-induced apoptosis

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Abstract
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.
Keywords
UNFOLDED-PROTEIN-RESPONSE, HUMAN-MELANOMA CELLS, LIGAND-INDUCED, APOPTOSIS, DEATH RECEPTOR 5, UP-REGULATION, ENDOPLASMIC-RETICULUM, MEDIATED APOPTOSIS, KAPPA-B, TUMORICIDAL ACTIVITY, DEPENDENT APOPTOSIS

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Citation

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Chicago
Estornes, Yann, Yves Dondelinger, Kathrin Weber, Inge Bruggeman, Adam Peall, Marion MacFarlane, Serge Lebecque, Peter Vandenabeele, and Mathieu Bertrand. 2018. “N-glycosylation of Mouse TRAIL-R Restrains TRAIL-induced Apoptosis.” Cell Death & Disease 9.
APA
Estornes, Y., Dondelinger, Y., Weber, K., Bruggeman, I., Peall, A., MacFarlane, M., Lebecque, S., et al. (2018). N-glycosylation of mouse TRAIL-R restrains TRAIL-induced apoptosis. CELL DEATH & DISEASE, 9.
Vancouver
1.
Estornes Y, Dondelinger Y, Weber K, Bruggeman I, Peall A, MacFarlane M, et al. N-glycosylation of mouse TRAIL-R restrains TRAIL-induced apoptosis. CELL DEATH & DISEASE. 2018;9.
MLA
Estornes, Yann, Yves Dondelinger, Kathrin Weber, et al. “N-glycosylation of Mouse TRAIL-R Restrains TRAIL-induced Apoptosis.” CELL DEATH & DISEASE 9 (2018): n. pag. Print.
@article{8563834,
  abstract     = {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.},
  articleno    = {494},
  author       = {Estornes, Yann and Dondelinger, Yves and Weber, Kathrin and Bruggeman, Inge and Peall, Adam and MacFarlane, Marion and Lebecque, Serge and Vandenabeele, Peter and Bertrand, Mathieu},
  issn         = {2041-4889},
  journal      = {CELL DEATH \& DISEASE},
  keyword      = {UNFOLDED-PROTEIN-RESPONSE,HUMAN-MELANOMA CELLS,LIGAND-INDUCED,APOPTOSIS,DEATH RECEPTOR 5,UP-REGULATION,ENDOPLASMIC-RETICULUM,MEDIATED APOPTOSIS,KAPPA-B,TUMORICIDAL ACTIVITY,DEPENDENT APOPTOSIS},
  language     = {eng},
  pages        = {13},
  title        = {N-glycosylation of mouse TRAIL-R restrains TRAIL-induced apoptosis},
  url          = {http://dx.doi.org/10.1038/s41419-018-0544-7},
  volume       = {9},
  year         = {2018},
}

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