In Situ Fucosylation of the Wnt Co-receptor LRP6 Increases Its Endocytosis and Reduces Wnt/β-Catenin Signaling. Issue 9 (17th September 2020)

• Record Type: Journal Article
• Authors: Hong, Senlian; Feng, Lei; Yang, Yi; Jiang, Hao; Hou, Xiaomeng; Guo, Peng; Marlow, Florence L.; Stanley, Pamela; Wu, Peng
• Is Part Of: Cell chemical biology. Volume 27:Issue 9(2020)
• Page Start: 1140
• Page End: 1150.e4
• Publication Date: 2020-09-17
• Subjects: (1–3)-fucosylation -- LRP6 -- Wnt signaling/β-catenin signaling -- endocytosis; Biochemistry -- Periodicals; 572.05
• DOI: 10.1016/j.chembiol.2020.06.015
• Languages: English
• ISSNs: 2451-9456

Abstract

Summary: Wnt/β-catenin signaling regulates critical, context-dependent transcription in numerous physiological events. Among the well-documented mechanisms affecting Wnt/β-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 [ISF]), we report that α(1–3)-fucosylation of N -acetylglucosamine (Glc N Ac) in the Galβ(1–4)-Glc N Ac sequences of complex N -glycans modulates Wnt/β-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/β-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. Graphical Abstract: Highlights: Increasing cell-surface α(1–3)-fucosylation suppresses Wnt/β-catenin signaling Increased α(1–3)-fucosylation elevates the endocytosis of lipid-raft-localized LRP6 Free fucose rescues the Wnt suppression induced by cell-surface α(1–3)-fucosylation Abstract : Hong et al. applied a chemenzymatic glycan editing approach to in situ elevate live cell-surface α(1–3)-fucosylation. This study revealed that increased α(1–3)-fucosylation increases the endocytosis of lipid-raft-localized LRP6, which in turn results in the decrease of LRP6-mediated Wnt signaling.