Rescue of Notch signaling in cells incapable of GDP-L-fucose synthesis by gap junction transfer of GDP-L-fucose in Drosophila
Rescue of Notch signaling in cells incapable of GDP-L-fucose synthesis by gap junction transfer of GDP-L-fucose in Drosophila
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DOI：
10.1073/pnas.1202369109
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发表时间：
2012-09-18
影响因子：
11.1
通讯作者：
Matsuno, Kenji
中科院分区：
文献类型：
--
作者：
Ayukawa, Tomonori;Matsumoto, Kenjiroo;Matsuno, Kenji
Noch(N)是一种跨膜受体，调节细胞与细胞之间的相互作用，决定许多细胞的命运。N含有EGF样重复序列，其中许多具有调节N-配体结合的O-岩藻糖糖修饰。这种修饰需要GDp-L-岩藻糖作为岩藻糖的供体。国内生产总值-L-岩藻糖的生物合成途径已被人们熟知，包括依赖于国内生产总值-甘露糖4，6-脱水酶和国内生产总值-4-酮-6-脱氧-D-甘露糖3，5-差向异构酶/4-还原酶的从头合成途径。然而，细胞间供应GDP一L-岩藻糖的潜力和这种运输的分子基础还没有被深入探讨。为了解决这些问题，我们研究了突变的GMD和Gmer对果蝇岩藻糖修饰的遗传效应。我们发现这些突变体的功能是非自主的，并且GDp-L-岩藻糖是通过由内联蛋白-2组成的缝隙连接提供给细胞的。GDP一L-岩藻糖不能通过不同器官的体液供应，说明GDP一L-岩藻糖在细胞内的分布受一定器官的限制。此外，缝隙连接介导的Gdp-L-岩藻糖供应足以支持N-糖链的岩藻糖化和N-EGF-like重复序列的O-岩藻糖化。我们的结果表明，在某些情况下，细胞间递送是活体动物体内核苷酸糖的代谢途径。
Notch (N) is a transmembrane receptor that mediates cell-cell interactions to determine many cell-fate decisions. N contains EGF-like repeats, many of which have an O-fucose glycan modification that regulates N-ligand binding. This modification requires GDP-L-fucose as a donor of fucose. The GDP-L-fucose biosynthetic pathways are well understood, including the de novo pathway, which depends on GDP-mannose 4,6 dehydratase (Gmd) and GDP-4-keto-6-deoxy-D-mannose 3,5-epimerase/4-reductase (Gmer). However, the potential for intercellularly supplied GDP-L-fucose and the molecular basis of such transportation have not been explored in depth. To address these points, we studied the genetic effects of mutating Gmd and Gmer on fucose modifications in Drosophila. We found that these mutants functioned cell-nonautonomously, and that GDP-L-fucose was supplied intercellularly through gap junctions composed of Innexin-2. GDP-L-fucose was not supplied through body fluids from different isolated organs, indicating that the intercellular distribution of GDP-L-fucose is restricted within a given organ. Moreover, the gap junction-mediated supply of GDP-L-fucose was sufficient to support the fucosylation of N-glycans and the O-fucosylation of the N EGF-like repeats. Our results indicate that intercellular delivery is a metabolic pathway for nucleotide sugars in live animals under certain circumstances.