Extension of lipid-linked oligosaccharides is a high-priority aspect of the unfolded protein response: endoplasmic reticulum stress in Type I congenital disorder of glycosylation fibroblasts.
Extension of lipid-linked oligosaccharides is a high-priority aspect of the unfolded protein response: endoplasmic reticulum stress in Type I congenital disorder of glycosylation fibroblasts.
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脂质连接寡糖的延伸是未折叠蛋白质反应的一个高度优先的方面：I型先天性糖基化成纤维细胞疾病中的内质网应激。
DOI：
10.1093/glycob/12.5.307
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发表时间：
2002
期刊：
影响因子：
4.3
通讯作者：
Lehrman,MarkA
中科院分区：
文献类型：
--
作者：
Shang,Jie;Körner,Christian;Freeze,Hudson;Lehrman,MarkA
内质网（ER）糖蛋白上的天冬酰胺（N）连接聚糖在蛋白质折叠和质量控制的多个方面具有关键作用。N-连接聚糖的前体脂联寡糖（LLO）合成的抑制导致糖蛋白错误折叠。这导致ER应激并触发未折叠蛋白反应（UPR），其由一组适应性事件或“方面”组成，包括LLO中间体的增强的延伸。I型先天性糖基化障碍（CDG）的特征在于LLO合成减少和异常N-糖基化。这种缺陷将被预测为导致慢性ER应激和持续的UPR激活。我们采用了定量药理学方法与真皮成纤维细胞，以显示（1）相比，其他三个众所周知的UPR方面（转录激活，抑制翻译，细胞死亡），LLO延伸是最敏感的ER应力;和（2）I型CDG细胞有一个温和的形式的慢性ER应力，其中LLO延伸持续应力激活，但其他方面的UPR是不变的。据我们所知，I型CDG是唯一的人类疾病，显示有慢性ER压力造成的遗传缺陷的ER质量控制system.In结论，LLO延伸具有较高的优先级，在UPR的真皮成纤维细胞。这表明细胞刺激N-糖基化作为抵抗ER功能障碍的第一道防线的一部分。这些结果的普遍定期审议的生物学意义的更广泛的影响进行了讨论。
Asparagine (N)-linked glycans on endoplasmic reticulum (ER) glycoproteins have critical roles in multiple facets of protein folding and quality control. Inhibition of synthesis of lipid-linked oligosaccharides (LLOs), the precursors of N-linked glycans, causes glycoprotein misfolding. This results in ER stress and triggers the unfolded protein response (UPR), which consists of a set of adaptive events, or “aspects,” including enhanced extension of LLO intermediates.Type I congenital disorders of glycosylation (CDGs) are characterized by diminished LLO synthesis and aberrant N-glycosylation. Such defects would be predicted to cause chronic ER stress with continuous UPR activation. We employed a quantitative pharmacological approach with dermal fibroblasts to show that (1) compared with three other well-known UPR aspects (transcriptional activation, inhibition of translation, and cell death), LLO extension was the most sensitive to ER stress; and (2) Type I CDG cells had a mild form of chronic ER stress in which LLO extension was continuously stress-activated, but other aspects of the UPR were unchanged. To our knowledge, Type I CDGs are the only human diseases shown to have chronic ER stress resulting from genetic defects in the ER quality control system.In conclusion, LLO extension has a high priority in the UPR of dermal fibroblasts. This suggests that cells stimulate N-glycosylation as part of a first line of defense against ER dysfunction. The broader implications of these results for the biological significance of the UPR are discussed.