Evading Death

Science Signaling  05 Jul 2011:
Vol. 4, Issue 180, pp. ec184
DOI: 10.1126/scisignal.4180ec184

Upon ligation, the Fas receptor assembles the death-inducing signaling complex (DISC). The first step in the assembly of the DISC is recruitment of the adaptor protein FADD (Fas-associated death domain protein) to Fas, which in turn elicits the recruitment and activation of initiator caspases (such as caspase 8) and effector caspases (such as caspases 3 and 7). Endocytosis of Fas is also required for effective apoptotic signaling. Swindall and Bellis found that Fas was a substrate for ST6Gal-I, a glycosyltransferase that adds sialic acid to the N-glycans of glycoproteins. Increased abundance of ST6Gal-I in various cancers, including colon carcinoma, correlates with metastasis and poor prognosis. Compared with HD3 colon carcinoma cells overexpressing STGGal-I (HD3.par cells), cells depleted of ST6Gal-I by stable expression of an shRNA (HD3.sh cells) showed increased apoptosis (as assessed by activation of caspases 3 and 7, nuclear condensation, and changes in cell morphology) in response to CH11, a Fas-activating antibody, but not in response to TRAIL, the ligand for death receptor 4 (DR4) and DR5. Similarly, greater activation of caspase 3 was detected in HD3.sh cells treated with FasL, the native ligand for Fas. Overexpression of ST6Gal-I protected SW48 colon epithelial cells (in which ST6Gal-I is not detectable) from apoptosis induced by FasL but not from that induced by TRAIL. Biochemical assays indicated that Fas was sialylated by ST6Gal-I, a modification that decreased recruitment of FADD to Fas (and thus DISC formation) and prevented internalization of Fas in CH11-treated cells. Thus, the high abundance of ST6Gal-I in colon carcinoma cells may enable them to evade Fas-induced apoptosis.

A. F. Swindall, S. L. Bellis, Sialylation of the Fas death receptor by ST6Gal-I provides protection against Fas-mediated apoptosis in colon carcinoma cells. J. Biol. Chem. 286, 22982–22990 (2011). [Abstract] [Full Text]