Journal
CELL CHEMICAL BIOLOGY
Volume 27, Issue 9, Pages 1140-+Publisher
CELL PRESS
DOI: 10.1016/j.chembiol.2020.06.015
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Funding
- National Institutes of Health (NIH, United States) [GM093282, GM113046, GM105399]
- National Cancer Institute (NCI, United States) Cancer Center grant [PO1 13330]
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Wnt/beta-catenin signaling regulates critical, context-dependent transcription in numerous physiological events. Among the well-documented mechanisms affecting Wnt/beta-catenin activity, modification of N-glycans by L-fucose is the newest and the least understood. Using a combination of Chinese hamster ovary cell mutants with different fucosylation levels and cell-surface fucose editing (in situ fucosylation [IU]), we report that alpha(1-3)-fucosylation of N-acetylglucosamine (GlcNAc) in the Gal beta(1-4)-GlcNAc sequences of complex N-glycans modulates Wnt/beta-catenin activity by regulating the endocytosis of low-density lipoprotein receptor-related protein 6 (LRP6). Pulse-chase experiments reveal that ISF elevates endocytosis of lipid-raft-localized LRP6, leading to the suppression of Wnt/beta-catenin signaling. Remarkably, Wnt activity decreased by ISF is fully reversed by the exogenously added fucose. The combined data show that in situ cell-surface fucosylation can be exploited to regulate a specific signaling pathway via endocytosis promoted by a fucose-binding protein, thereby linking glycosylation of a receptor with its intracellular signaling.
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