Metabolically programmed quality control system for dolichol-linked oligosaccharides
Metabolically programmed quality control system for dolichol-linked oligosaccharides
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DOI：
10.1073/pnas.1312187110
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发表时间：
2013-11-26
影响因子：
11.1
通讯作者：
Suzuki, Tadashi
中科院分区：
文献类型：
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作者：
Harada, Yoichiro;Nakajima, Kazuki;Suzuki, Tadashi
糖脂Glc（3）Man（9）GlcNAc（2）-焦磷酸-多萜醇作为哺乳动物中天冬酰胺（N）-连接的蛋白质糖基化的前体。在低葡萄糖环境中，长链寡糖（DLO）的生物合成通过未知的机制被阻止，导致异常的N-糖基化。在这里，我们表明，在葡萄糖剥夺，DLO过早降解DLO生物合成的早期阶段，由焦磷酸酶，导致单磷酸化寡糖释放到胞质溶胶。我们发现，作为DLO生物合成的供体底物的GDP-甘露糖（Man）的水平在葡萄糖剥夺下显著降低。我们提供的证据表明，GDP-Man生物合成途径的选择性关闭足以诱导磷酸化寡糖的释放。这些结果表明，GDP-Man生物合成途径中葡萄糖调节的代谢变化导致DLO的生物合成停滞，并促进其被焦磷酸酶过早降解。我们建议，这种降解系统可以避免异常的N-糖基化与过早的寡糖的条件下，损害有效的DLO生物合成。
The glycolipid Glc(3)Man(9)GlcNAc(2)-pyrophosphate-dolichol serves as the precursor for asparagine (N)-linked protein glycosylation in mammals. The biosynthesis of dolichol-linked oligosaccharides (DLOs) is arrested in low-glucose environments via unknown mechanisms, resulting in abnormal N-glycosylation. Here, we show that under glucose deprivation, DLOs are prematurely degraded during the early stages of DLO biosynthesis by pyrophosphatase, leading to the release of singly phosphorylated oligosaccharides into the cytosol. We identified that the level of GDP-mannose (Man), which serves as a donor substrate for DLO biosynthesis, is substantially reduced under glucose deprivation. We provide evidence that the selective shutdown of the GDP-Man biosynthetic pathway is sufficient to induce the release of phosphorylated oligosaccharides. These results indicate that glucose-regulated metabolic changes in the GDP-Man biosynthetic pathway cause the biosynthetic arrest of DLOs and facilitate their premature degradation by pyrophosphatase. We propose that this degradation system may avoid abnormal N-glycosylation with premature oligosaccharides under conditions that impair efficient DLO biosynthesis.