Forcible destruction of severely misfolded mammalian glycoproteins by the non-glycoprotein ERAD pathway.
Forcible destruction of severely misfolded mammalian glycoproteins by the non-glycoprotein ERAD pathway.
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DOI：
10.1083/jcb.201504109
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发表时间：
2015-11-23
期刊：
影响因子：
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通讯作者：
Mori K
中科院分区：
文献类型：
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作者：
Ninagawa S;Okada T;Sumitomo Y;Horimoto S;Sugimoto T;Ishikawa T;Takeda S;Yamamoto T;Suzuki T;Kamiya Y;Kato K;Mori K
高等真核生物，而不是酵母，能够从内质网相关降解（ERAD）途径提取严重错误折叠的糖蛋白的糖蛋白，并将其靶向ERAD途径的非糖蛋白，以维持ER的稳态。内质网相关降解（ERAD）-L以不同的机制从内质网（ER）中清除在其管腔区域具有未折叠/错误折叠部分的糖蛋白和非糖蛋白。从Man 9 GlcNAc 2进行两步甘露糖修剪在糖蛋白的ERAD-L中至关重要。我们最近发现，这个过程是由EDEM 2启动，并由EDEM 3/EDEM 1完成。在这里，我们构建了鸡和人细胞同时缺乏EDEM 1/2/3和分析的命运四ERAD-L基板含有三个潜在的N-糖基化位点。我们发现，天然但不稳定或有些未折叠的糖蛋白，如ATF 6 α，ATF 6 α（C），CD 3-δ-ΔTM和EMC 1，在EDEM 1/2/3三重敲除细胞中稳定。与此形成鲜明对比的是，严重错误折叠的糖蛋白（如空香港（NHK）和ATF 6 α（C）、CD 3-δ-ΔTM和EMC 1的缺失或插入突变体）的降解仅在早期追踪期延迟，但它们最终与野生型细胞一样降解。因此，高等真核生物能够从糖蛋白ERAD中提取严重错误折叠的糖蛋白，并将其靶向非糖蛋白ERAD途径以维持ER的稳态。
Higher eukaryotes, but not yeast, are able to extract severely misfolded glycoproteins from the endoplasmic reticulum–associated degradation (ERAD) pathway for glycoproteins and target them to the ERAD pathway for non-glycoproteins to maintain the homeostasis of the ER. Glycoproteins and non-glycoproteins possessing unfolded/misfolded parts in their luminal regions are cleared from the endoplasmic reticulum (ER) by ER-associated degradation (ERAD)-L with distinct mechanisms. Two-step mannose trimming from Man9GlcNAc2 is crucial in the ERAD-L of glycoproteins. We recently showed that this process is initiated by EDEM2 and completed by EDEM3/EDEM1. Here, we constructed chicken and human cells simultaneously deficient in EDEM1/2/3 and analyzed the fates of four ERAD-L substrates containing three potential N-glycosylation sites. We found that native but unstable or somewhat unfolded glycoproteins, such as ATF6α, ATF6α(C), CD3-δ–ΔTM, and EMC1, were stabilized in EDEM1/2/3 triple knockout cells. In marked contrast, degradation of severely misfolded glycoproteins, such as null Hong Kong (NHK) and deletion or insertion mutants of ATF6α(C), CD3-δ–ΔTM, and EMC1, was delayed only at early chase periods, but they were eventually degraded as in wild-type cells. Thus, higher eukaryotes are able to extract severely misfolded glycoproteins from glycoprotein ERAD and target them to the non-glycoprotein ERAD pathway to maintain the homeostasis of the ER.