RRC ID 31024
Author Ishikawa HO, Ayukawa T, Nakayama M, Higashi S, Kamiyama S, Nishihara S, Aoki K, Ishida N, Sanai Y, Matsuno K.
Title Two pathways for importing GDP-fucose into the endoplasmic reticulum lumen function redundantly in the O-fucosylation of Notch in Drosophila.
Journal J Biol Chem
Abstract Notch is a transmembrane receptor that shares homology with proteins containing epidermal growth factor-like repeats and mediates the cell-cell interactions necessary for many cell fate decisions. In Drosophila, O-fucosyltransferase 1 catalyzes the O-fucosylation of these epidermal growth factor-like repeats. This O-fucose elongates, resulting in an O-linked tetrasaccharide that regulates the signaling activities of Notch. Fucosyltransferases utilize GDP-fucose, which is synthesized in the cytosol, but fucosylation occurs in the lumen of the endoplasmic reticulum (ER) and Golgi. Therefore, GDP-fucose uptake into the ER and Golgi is essential for fucosylation. However, although GDP-fucose biosynthesis is well understood, the mechanisms and intracellular routes of GDP-fucose transportation remain unclear. Our previous study on the Drosophila Golgi GDP-fucose transporter (Gfr), which specifically localizes to the Golgi, suggested that another GDP-fucose transporter(s) exists in Drosophila. Here, we identified Efr (ER GDP-fucose transporter), a GDP-fucose transporter that localizes specifically to the ER. Efr is a multifunctional nucleotide sugar transporter involved in the biosynthesis of heparan sulfate-glycosaminoglycan chains and the O-fucosylation of Notch. Comparison of the fucosylation defects in the N-glycans in Gfr and Efr mutants revealed that Gfr and Efr made distinct contributions to this modification; Gfr but not Efr was crucial for the fucosylation of N-glycans. We also found that Gfr and Efr function redundantly in the O-fucosylation of Notch, although they had different localizations and nucleotide sugar transportation specificities. These results indicate that two pathways for the nucleotide sugar supply, involving two nucleotide sugar transporters with distinct characteristics and distributions, contribute to the O-fucosylation of Notch.
Volume 285(6)
Pages 4122-4129
Published 2010-2-5
DOI 10.1074/jbc.M109.016964
PII S0021-9258(20)81082-5
PMID 19948734
PMC PMC2823552
MeSH Animals Biological Transport Blotting, Western Drosophila Proteins / genetics Drosophila Proteins / metabolism* Drosophila melanogaster / genetics Drosophila melanogaster / metabolism* Endoplasmic Reticulum / metabolism* Glycosaminoglycans / biosynthesis Glycosylation Golgi Apparatus / metabolism Guanosine Diphosphate Fucose / metabolism* Immunohistochemistry Monosaccharide Transport Proteins / genetics Monosaccharide Transport Proteins / metabolism Mutation Nucleotide Transport Proteins / genetics Nucleotide Transport Proteins / metabolism Polysaccharides / metabolism Receptors, Notch / genetics Receptors, Notch / metabolism* Signal Transduction
IF 4.238
Times Cited 31