Editors' ChoiceGlycosylation

Fucosylation Required for TGF-β Receptor Function

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Science's STKE  08 Nov 2005:
Vol. 2005, Issue 309, pp. tw391
DOI: 10.1126/stke.3092005tw391

Wang et al. engineered Fut8 knockout mice lacking the α1,6-fucosyltransferase that catalyzes the addition of fucose to the sugar core of glycoproteins. These mice exhibited increased postnatal mortality, and surviving pups showed retarded growth and had emphysema-like changes to the lung. Loss of core fucosylation decreased signaling by several receptors. The lung phenotype--increased expression of the genes encoding metalloproteinases MMP-12, MMP-13, and the mouse homolog of MMP-1 (resulting in their increased activity in lung tissue and fibroblasts) and decreased expression of genes encoding elastin--was consistent with a loss of transforming growth factor-β (TGF-β) signaling. Binding of TGF-β1 to Fut8–/– fibroblasts was reduced compared with that in wild-type cells, and TGF-β1 failed to inhibit increased secretion of MMP-12 in response to interleukin-1β (IL-1β). Lectin-binding assays confirmed that TGF-β type II receptor fucosylation was decreased in Fut8–/– cells and phosphorylation of Smad2 in the lung tissue of Fut8–/– mice was decreased compared with that in lungs of wild-type mice. Finally, the emphysema-like phenotype was rescued by injection of the newborn mice with TGF-β1. Schachter discusses these results and the importance of glycosylation in human diseases.

X. Wang, S. Inoue, J. Gu, E. Miyoshi, K. Noda, W. Li, Y. Mizuno-Horikawa, M. Nakano, M. Asahi, M. Takahashi, N. Uozumi, S. Ihara, S. H. Lee, Y. Ikeda, Y. Yamaguchi, Y. Aze, Y. Tomiyama, J. Fujii, K. Suzuki, A. Kondo, S. D. Shapiro, C. Lopez-Otin, T. Kuwaki, M. Okabe, K. Honke, N. Taniguchi, Dysregulation of TGF-1 receptor activation leads to abnormal lung development and emphysema-like phenotype in core fucose-deficient mice. Proc. Natl. Acad. Sci. U. S. A. 102, 15791-15796 (2005). [Abstract] [Full Text]

H. Schachter, The search for glycan function: Fucosylation of the TGF-β1 receptor is required for receptor activation. Proc. Natl. Acad. Sci. U.S.A. 102, 15721-15722 (2005). [Full Text]

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