Abstract
Tumor necrosis-factor related apoptosis-inducing ligand, also known as TRAIL or APO2L (Apo-2 ligand), is a cytokine of the TNF superfamily acknowledged for its ability to trigger selective apoptosis in tumor cells while being relatively safe towards normal cells. Its binding to its cognate agonist receptors, namely death receptor 4 (DR4) and/or DR5, can induce the formation of a membrane-bound macromolecular complex, coined DISC (death-signaling inducing complex), necessary and sufficient to engage the apoptotic machinery. At the very proximal level, TRAIL DISC formation and activation of apoptosis is regulated both by antagonist receptors and by glycosylation. Remarkably, though, despite the fact that all membrane-bound TRAIL receptors harbor putative glycosylation sites, only pro-apoptotic signaling through DR4 and DR5 has, so far, been found to be regulated by N- and O-glycosylation, respectively. Because putative N-glycosylation sequons and O-glycosylation sites are also found and conserved in all these receptors throughout all animal species (in which these receptors have been identified), glycosylation is likely to play a more prominent role than anticipated in regulating receptor/receptor interactions or trafficking, ultimately defining cell fate through TRAIL stimulation. This review aims to present and discuss these emerging concepts, the comprehension of which is likely to lead to innovative anticancer therapies.
Highlights
All ligands and receptors of the TNF superfamily, with the exception of TRAIL (TNF-Related apoptosis-inducing ligand or APO2L), harbor putative N- and/or O-linked glycosylation sites [1]
The authors of this study demonstrated that fucosylation of death receptor 4 (DR4), but not DR5, restored TRAIL sensitivity in these cells [71]
Investigators have been searching a long time for an explanation for the lack of self-receptor aggregation at the cell surface, explaining why cells harboring the latter fail to undergo spontaneous apoptosis in the absence of the ligand
Summary
All ligands and receptors of the TNF superfamily, with the exception of TRAIL (TNF-Related apoptosis-inducing ligand or APO2L), harbor putative N- and/or O-linked glycosylation sites [1]. The most abundantly occurring forms of carbohydrate modifications are linked to asparagine (Asn) [3] and serine (Ser) or threonine (Thr) amino acids [4] These carbohydrate chains are not solely involved in protein folding control—i.e., ensuring proper synthesis of polypeptides prior to their addressing at the cell surface or secretion—but are directly involved in the fine-tuning of membrane-bound receptor signaling capabilities. They could affect TRAIL receptors directly by changing the folding or flexibility of the cysteine-rich domain (CRD), similar to the recent findings on the ectodomain of the LDL-receptor-related protein 6 (LRP6), the N-glycosylation of which was found to be critical to its folding and aggregation potential [5]. Since most membrane-bound proteins harbor these post-translational modifications, carbohydrate chains may allow unexpected glycoprotein/glycoprotein interactions, resulting in the positive or negative regulation of a given pathway and, in particular, signal transduction induced by TRAIL receptors
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