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Two Pathways for Importing GDP-fucose into the Endoplasmic Reticulum Lumen Function Redundantly in the O-Fucosylation of Notch in Drosophila*

机译:果蝇凹口的O-岩藻糖基化过程中将GDP-岩藻糖导入内质网腔功能的两种途径*

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摘要

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.
机译:Notch是一种跨膜受体,与包含表皮生长因子样重复序列的蛋白质具有同源性,并介导许多细胞命运决定所必需的细胞间相互作用。在果蝇中,O-岩藻糖基转移酶1催化这些表皮生长因子样重复序列的O-岩藻糖基化。该O-岩藻糖伸长,产生调节Notch信号传导活性的O-连接的四糖。岩藻糖基转移酶利用GDP-岩藻糖,其在细胞质中合成,但是岩藻糖基化发生在内质网(ER)和高尔基体腔中。因此,岩藻糖基化对ER和高尔基的GDP岩藻糖摄取至关重要。然而,尽管GDP-岩藻糖的生物合成已广为人知,但GDP-岩藻糖运输的机制和细胞内途径仍不清楚。我们之前对果蝇高尔基GDP-岩藻糖转运蛋白(Gfr)的研究特别是定位于高尔基体,这表明果蝇中还存在另一种GDP-岩藻糖转运蛋白。在这里,我们确定了Efr(ER GDP-岩藻糖转运蛋白),这是专门针对ER的GDP-岩藻糖转运蛋白。 Efr是一种多功能核苷酸糖转运蛋白,参与硫酸乙酰肝素-糖胺聚糖链的生物合成和Notch的O-岩藻糖基化。比较Gfr和Efr突变体中N-聚糖的岩藻糖基化缺陷,发现Gfr和Efr对这种修饰做出了独特的贡献。 Gfr但不是Efr对N-聚糖的岩藻糖基化至关重要。我们还发现,Gfr和Efr在Notch的O-岩藻糖基化中具有多余的功能,尽管它们具有不同的定位和核苷酸糖转运特异性。这些结果表明核苷酸糖供应的两个途径,涉及具有不同特征和分布的两个核苷酸糖转运蛋白,对Notch的O-岩藻糖基化起作用。

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