N-glycosylation of mouse TRAIL-R restrains TRAIL-induced apoptosis.
N-glycosylation of mouse TRAIL-R restrains TRAIL-induced apoptosis.
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DOI：
10.1038/s41419-018-0544-7
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发表时间：
2018-05-01
影响因子：
9
通讯作者：
Bertrand MJM
中科院分区：
文献类型：
--
作者：
Estornes Y;Dondelinger Y;Weber K;Bruggeman I;Peall A;MacFarlane M;Lebecque S;Vandenabeele P;Bertrand MJM
细胞对死亡受体诱导的细胞凋亡的敏感性通常由多个检查点控制，以限制诱导过度或不必要的死亡。尽管肿瘤坏死因子（TNF）相关凋亡诱导配体（TRAIL）在多种癌细胞中具有细胞毒性，但在大多数非转化细胞中不会引发凋亡。通常保护细胞免于TRAIL诱导的死亡的检查点的分子性质尚未完全理解。据报道，内质网（ER）应激可使人细胞对TRAIL的细胞毒性作用的敏感性发生改变，这表明这种细胞状态扰乱了其中一些保护机制。我们发现衣霉素（TU），但没有其他ER应激诱导剂，敏化小鼠成纤维细胞和海马神经元细胞TRAIL诱导的凋亡。重要的是，致敏是特异性的TRAIL，而不是由ER应激诱导的差异引起的。相反，它依赖于抑制小鼠TRAIL受体（mTRAIL-R）的N-糖基化。抑制N-糖基化并不改变mTRAIL-R的细胞表面表达，但增强了其结合TRAIL的能力，并促进mTRAIL-R寡聚化，这导致增强的死亡诱导信号复合物（DISC）形成和caspase-8激活。值得注意的是，mTRAIL-R缺陷细胞与突变的mTRAIL-R的版本在其胞外域鉴定的三个N-糖基化位点的重建证实了对TRAIL诱导的细胞凋亡的更高的敏感性。总之，我们的结果表明，抑制mTRAIL-R的N-糖基化，而不是ER应激诱导，使小鼠细胞对TRAIL诱导的细胞凋亡敏感。因此，我们揭示了一种新的机制，抑制小鼠细胞中的TRAIL细胞毒性。
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.
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