EDEM2 initiates mammalian glycoprotein ERAD by catalyzing the first mannose trimming step.
EDEM2 initiates mammalian glycoprotein ERAD by catalyzing the first mannose trimming step.
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DOI：
10.1083/jcb.201404075
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发表时间：
2014-08-04
期刊：
影响因子：
--
通讯作者：
Mori K
中科院分区：
文献类型：
--
作者：
Ninagawa S;Okada T;Sumitomo Y;Kamiya Y;Kato K;Horimoto S;Ishikawa T;Takeda S;Sakuma T;Yamamoto T;Mori K
所有三种哺乳动物EDEM家族成员都具有甘露糖苷酶活性，并且是糖蛋白降解所必需的，但是EDEM 2在EDEM 1和EDEM 3的上游执行独特的、限速的第一个甘露糖修剪步骤。内质网（ER）中错误折叠的糖蛋白发生ER相关糖蛋白降解（gpERAD），其中Htm 1介导的甘露糖从寡糖Man 8 GlcNAc 2修剪为Man 7 GlcNAc 2是酵母中的限速步骤。相比之下，哺乳动物gpERAD中的三个Htm 1同源物（EDEM 1/2/3）的作用仍然难以捉摸，一个关键的争议是EDEM是否作为甘露聚糖酶或凝集素的功能。因此，我们在人类细胞系中进行了转录激活因子样效应物核酸酶介导的基因敲除分析，发现所有内源性EDEMs都具有甘露糖苷酶活性。从Man 8 GlcNAc 2到Man 7 GlcNAc 2的甘露糖修剪主要由EDEM 3进行，并且在较小程度上由EDEM 1进行。最令人惊讶的是，从Man 9 GlcNAc 2到Man 8 GlcNAc 2的上游甘露糖修剪主要通过EDEM 2进行，其先前被认为缺乏酶活性。基于哺乳动物gpERAD中存在两个限速步骤，我们建议哺乳动物细胞在破坏前通过进化EDEM 2（一种新型Htm 1同系物，催化Man 9 GlcNAc 2的第一个甘露糖修剪步骤）双重检查gpERAD底物。
All three mammalian EDEM family members possess mannosidase activity and are necessary for glycoprotein degradation, but EDEM2 performs a unique, rate-limiting, first mannose trimming step upstream of EDEM1 and EDEM3. Glycoproteins misfolded in the endoplasmic reticulum (ER) are subjected to ER-associated glycoprotein degradation (gpERAD) in which Htm1-mediated mannose trimming from the oligosaccharide Man8GlcNAc2 to Man7GlcNAc2 is the rate-limiting step in yeast. In contrast, the roles of the three Htm1 homologues (EDEM1/2/3) in mammalian gpERAD have remained elusive, with a key controversy being whether EDEMs function as mannosidases or as lectins. We therefore conducted transcription activator-like effector nuclease–mediated gene knockout analysis in human cell line and found that all endogenous EDEMs possess mannosidase activity. Mannose trimming from Man8GlcNAc2 to Man7GlcNAc2 is performed mainly by EDEM3 and to a lesser extent by EDEM1. Most surprisingly, the upstream mannose trimming from Man9GlcNAc2 to Man8GlcNAc2 is conducted mainly by EDEM2, which was previously considered to lack enzymatic activity. Based on the presence of two rate-limiting steps in mammalian gpERAD, we propose that mammalian cells double check gpERAD substrates before destruction by evolving EDEM2, a novel-type Htm1 homologue that catalyzes the first mannose trimming step from Man9GlcNAc2.
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