Mannose-6-phosphate regulates destruction of lipid-linked oligosaccharides
Mannose-6-phosphate regulates destruction of lipid-linked oligosaccharides
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DOI：
10.1091/mbc.e11-04-0286
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发表时间：
2011-09-01
影响因子：
3.3
通讯作者：
Lehrman, Mark A.
中科院分区：
文献类型：
--
作者：
Gao, Ningguo;Shang, Jie;Lehrman, Mark A.
甘露糖-6-磷酸（M6P）是甘露糖基糖缀合物的重要前体，包括用于蛋白质n糖基化的脂联寡糖（LLO）；葡萄糖(3)甘露糖（9)GlcNAc(2)- p -p -醇）。在通透性的哺乳动物细胞中，M6P也会引起特异性的LLO切割。然而，这种矛盾反应的背景和目的尚不清楚。在这项研究中，我们使用完整的小鼠胚胎成纤维细胞来证明内质网（ER）应激会升高M6P浓度，导致LLO焦磷酸链的断裂，并恢复其脂质和管腔聚糖成分。我们证明这种M6P来源于糖原，糖原分解被应激传感器ire1 - α的激酶结构域激活。M6P导致其LLO产物破坏的明显无效性通过另一种应力传感器——pkr样ER激酶（PERK）的实验得到了解决，该传感器减弱了翻译。PERK减少了n -糖蛋白合成（消耗LLOs），稳定了稳态LLO水平，尽管LLO持续破坏。然而，单纯疱疹病毒1（一种携带n糖蛋白的病原体，可损害PERK信号）的感染不仅会导致LLO破坏，还会降低LLO水平。总之，常见的代谢物M6P也是一种新的哺乳动物应激信号通路的一部分，通过消耗病毒相关多肽n -糖基化所需的宿主LLOs来响应病毒应激。在整个进化过程中，LLO的破坏显然是对各种环境压力的反应。
Mannose-6-phosphate (M6P) is an essential precursor for mannosyl glycoconjugates, including lipid-linked oligosaccharides (LLO; glucose(3)mannose(9)GlcNAc(2)-P-P-dolichol) used for protein N-glycosylation. In permeabilized mammalian cells, M6P also causes specific LLO cleavage. However, the context and purpose of this paradoxical reaction are unknown. In this study, we used intact mouse embryonic fibroblasts to show that endoplasmic reticulum (ER) stress elevates M6P concentrations, leading to cleavage of the LLO pyrophosphate linkage with recovery of its lipid and lumenal glycan components. We demonstrate that this M6P originates from glycogen, with glycogenolysis activated by the kinase domain of the stress sensor IRE1-alpha. The apparent futility of M6P causing destruction of its LLO product was resolved by experiments with another stress sensor, PKR-like ER kinase (PERK), which attenuates translation. PERK's reduction of N-glycoprotein synthesis (which consumes LLOs) stabilized steady-state LLO levels despite continuous LLO destruction. However, infection with herpes simplex virus 1, an N-glycoprotein-bearing pathogen that impairs PERK signaling, not only caused LLO destruction but depleted LLO levels as well. In conclusion, the common metabolite M6P is also part of a novel mammalian stress-signaling pathway, responding to viral stress by depleting host LLOs required for N-glycosylation of virus-associated polypeptides. Apparently conserved throughout evolution, LLO destruction may be a response to a variety of environmental stresses.