STT3B-Dependent Posttranslational N-Glycosylation as a Surveillance System for Secretory Protein
STT3B-Dependent Posttranslational N-Glycosylation as a Surveillance System for Secretory Protein
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DOI：
10.1016/j.molcel.2012.04.015
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发表时间：
2012-07-13
期刊：
影响因子：
16
通讯作者：
Kai, Hirofumi
中科院分区：
文献类型：
--
作者：
Sato, Takashi;Sako, Yasuhiro;Kai, Hirofumi
新生的分泌蛋白在胞质网 (ER) 中受到广泛的检查。协调利用客户蛋白的各种特征，包括疏水斑块或未配对的巯基的暴露，以减少内质网中的非天然蛋白。我们在这里报告了神秘的 N-糖基化位点，作为一种识别信号，用于展开与家族性淀粉样变性有关的天然非糖基化蛋白运甲状腺素蛋白 (TTR)。折叠和 ER 相关降解 (ERAD) 扰动分析表明，延长的 TTR 解折叠会诱导隐藏的 N-糖基化位点的外化，并触发依赖于 STT3B 的翻译后 N-糖基化。抑制翻译后 N-糖基化会增加去污剂不溶性 TTR 聚集体，并降低表达突变 TTR 的细胞的细胞增殖。此外，这种修饰提供了另一种降解途径，即EDErVI3介导的N-聚糖依赖性ERAD，与Herp介导的N-聚糖非依赖性ERAD的主要途径不同。因此，我们假设 SIT3B 依赖性翻译后 N-糖基化是分类挽救系统的一部分，该系统识别分泌蛋白的隐性 N-糖基化位点以保持蛋白质稳态。
Nascent secretory proteins are extensively scrutinized at the encioplasmic reticulum (ER). Various signatures of client proteins, including exposure of hydrophobic patches or unpaired sulfhydryls, are coordinately utilized to reduce nonnative proteins in the ER. We report here the cryptic N-glycosylation site as a recognition signal for unfolding of a natively nonglycosylated protein, transthyretin (TTR), involved in familial amyloidosis. Folding and ER-associated degradation (ERAD) perturbation analyses revealed that prolonged TTR unfolding induces externalization of cryptic N-glycosylation site and triggers STT3B-depenclent posttranslational N-glycosylation. Inhibition of posttranslational N-glycosylation increases detergent-insoluble TTR aggregates and decreases cell proliferation of mutant TTR-expressing cells. Moreover, this modification provides an alternative pathway for degradation, which is EDErVI3-mediated N-glycan-dependent ERAD, distinct from the major pathway of Herpmediated N-glycan-independent ERAD. Hence we postulate that SIT3B-dependent posttranslational N-glycosylation is part of a triage-salvage system recognizing cryptic N-glycosylation sites of secretory proteins to preserve protein homeostasis.