Post-translational modification of death receptors

Molecular oncology. Causes of cancer and targets for treatment. Cambridge University Press (2014)

Post-translational modifications of death receptors can play an important role in regulating the extrinsic apoptosis pathway. Like other cell-surface proteins, death receptors are glycosylated, including O-glycosylation with glycans attached to serine/threonine, and N-glycosylation that occurs at asparagine. O-glycosylation of TRAIL-R1 and TRAIL-R2 is reported to sensitize tumor cells to TRAIL-induced apoptosis (55). Depletion of the O-glycosylation-initiating enzyme GALNT14 decreases caspase-8 activity, while over-expression of GALNT14 augments caspase-8 activation at the DISC through promoting death-receptor clustering (55). In contrast to O-glycosylation of TRAIL-R1/R2, N-glycosylation of Fas has very modest effects on DISC formation (56). Nevertheless, Fas is shown to be sialylated on the N-glycans by the glycosyltransferase ST6Gal-I and the sialylation of Fas inhibits the DISC formation by blocking the Fas-FADD interaction (57–59).

Fas can be S-palmitoylated at a cysteine residue in its cytoplasmic region, which allows Fas to associate with the cytoskeleton-linked lipid rafts and is required for efficient Fas internalization and subsequent death signaling (60–61). TRAIL-R1 (but not TRAIL-R2) also can be S-palmitoylated at a cysteine triplet between the transmembrane domain of the DD. Palmitoylation of TRAIL-R1 is essential for its lipid-raft localization and oligomerization (62).


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