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O‐glycans on death receptors in cells modulate their sensitivity to TRAIL‐induced apoptosis through affecting on their stability and oligomerization
Author(s) -
Jiang Yuliang,
Wen Tao,
Yan Rui,
Kim Suryun,
Stowell Sean R.,
Wang Wenyi,
Wang Yingchun,
An Guangyu,
Cummings Richard D.,
Ju Tongzhong
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201900053rr
Subject(s) - apoptosis , receptor , microbiology and biotechnology , chemistry , glycan , sensitivity (control systems) , programmed cell death , biology , biochemistry , glycoprotein , engineering , electronic engineering
The TNF‐related apoptosis‐inducing ligand (TRAIL) triggers apoptosis in cells by signaling through the O‐glycosylated death receptors (DR4 and DR5), but the sensitivity to TRAIL‐induced apoptosis of cells varies, and the attributes of this phenomenon are complex. Human carcinoma cells often express truncated O‐glycans, Tn (GalNAcα1‐Ser/Thr), and Sialyl‐Tn (Siaα2‐6GalNAcα1‐Ser/Thr, STn) on their surface glycoproteins, yet molecular mechanisms in terms of advantages for tumor cells to have these truncated O‐glycans remain elusive. Normal extended O‐glycan biosynthesis is regulated by a specific molecular chaperone Cosmc through assisting of the correct folding of Core 1 β3 Galactosyltransferase (T‐synthase). Here, we use tumor cell lines harboring mutations in Cosmc, and therefore expressing Tn and STn antigens to study the role of O‐glycans in TRAIL‐induced apoptosis. Expression of Tn and STn in tumor cells attenuates their sensitivity to TRAIL treatment; when transfected with wild‐type Cosmc , these tumor cells thus express normal extended O‐glycans and become more sensitive to TRAIL treatment. Mechanistically, Tn/STn antigens impair homo‐oligomerization and stability of DR4 and DR5. These results represent the first mechanistic insight into how O‐glycan structures on cell surface modulate their sensitivity to apoptotic stimuli, suggesting expression of Tn/STn may offer tumor cell survival advantages through altering DR4 and/or DR5 activity.