Role of N-linked oligosaccharides in the biosynthetic processing of the cystic fibrosis membrane conductance regulator.
Role of N-linked oligosaccharides in the biosynthetic processing of the cystic fibrosis membrane conductance regulator.
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DOI：
10.1242/jcs.028951
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发表时间：
2008-09-01
影响因子：
4
通讯作者：
Gentzsch M
中科院分区：
文献类型：
--
作者：
Chang XB;Mengos A;Hou YX;Cui L;Jensen TJ;Aleksandrov A;Riordan JR;Gentzsch M
上皮氯离子通道 CFTR 是一种由两个 N 连接寡糖修饰的糖蛋白。囊性纤维化患者中最常见的突变 CFTR 蛋白 ΔF508 被错误折叠并被 ER 质量控制保留。由于已知糖蛋白的寡糖部分可介导与 ER 凝集素伴侣的相互作用，因此我们研究了 N 连接糖基化在野生型和 ΔF508 CFTR 加工中的作用。我们发现 N-糖基化和 ER 凝集素相互作用并不是野生型和 ΔF508 从 ER 运输到质膜的主要决定因素。通过去除糖基化位点或用 N-糖基化抑制剂衣霉素处理细胞产生的未糖基化 CFTR 不结合钙联蛋白，但会运输到细胞表面并表现出氯离子通道活性。最重要的是，未糖基化的 Δ F508 CFTR 仍然无法逃脱早期分泌途径的质量控制，并且仍然与 ER 相关。然而，N-连接寡糖的缺失确实降低了野生型 CFTR 的稳定性，导致 ER 后区室的周转速度显着加快。令人惊讶的是，单个 N 连接碳水化合物在野生型蛋白质的早期生物合成途径中并没有发挥同等的作用，并以不同的方式调节其命运。
The epithelial chloride channel CFTR is a glycoprotein that is modified by two N-linked oligosaccharides. The most common mutant CFTR protein in patients with cystic fibrosis, ΔF508, is misfolded and retained by ER quality control. As oligosaccharide moieties of glycoproteins are known to mediate interactions with ER lectin chaperones, we investigated the role of N-linked glycosylation in the processing of wild-type and ΔF508 CFTR. We found that N-glycosylation and ER lectin interactions are not major determinants of trafficking of wild-type and ΔF508 from the ER to the plasma membrane. Unglycosylated CFTR, generated by removal of glycosylation sites or treatment of cells with the N-glycosylation inhibitor tunicamycin, did not bind calnexin, but did traffic to the cell surface and exhibited chloride channel activity. Most importantly, unglycosylated Δ F508 CFTR still could not escape quality control in the early secretory pathway and remained associated with the ER. However, the absence of N-linked oligosaccharides did reduce the stability of wild-type CFTR, causing significantly more-rapid turnover in post-ER compartments. Surprisingly, the individual N-linked carbohydrates do not play equivalent roles and modulate the fate of the wild-type protein in different ways in its early biosynthetic pathway.
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影响因子：
3.5
作者：
Brothers, Shaun P.;Janovick, Jo Ann;Conn, P. Michael
通讯作者：
Conn, P. Michael
影响因子：
56.9
作者：
Egan, ME;Pearson, M;Caplan, MJ
通讯作者：
Caplan, MJ
DOI：
10.1016/j.bbrc.2006.12.036
发表时间：
2007-02-09
影响因子：
3.1
作者：
Harada, Kazutsune;Okiyoneda, Tsukasa;Kai, Hirofumi
通讯作者：
Kai, Hirofumi
影响因子：
64.8
作者：
DALEMANS, W;BARBRY, P;LAZDUNSKI, M
通讯作者：
LAZDUNSKI, M
影响因子：
3.5
作者：
Aleksandrov, AA;Riordan, JR
通讯作者：
Riordan, JR