Role of Drosophila EDEMs in the degradation of the alpha-1-antitrypsin Z variant.
Role of Drosophila EDEMs in the degradation of the alpha-1-antitrypsin Z variant.
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果蝇EDEM在α-1-抗抗蛋白酶Z变体降解中的作用。
DOI：
10.3892/ijmm.2015.2109
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发表时间：
2015-04
影响因子：
5.4
通讯作者：
Kang MJ
中科院分区：
文献类型：
--
作者：
Jang BY;Ryoo HD;Son J;Choi KC;Shin DM;Kang SW;Kang MJ
内质网（ER）中超过该细胞器蛋白质折叠能力的蛋白质合成是细胞功能障碍和疾病的常见原因。这种疾病的一个例子是α-1-抗胰蛋白酶（A1 AT）缺乏症，由这种糖蛋白的不稳定突变引起。据认为，突变蛋白在ER中被凝集素识别，随后通过蛋白酶体降解，导致患病患者中这种酶的缺乏。我们先前通过过表达该基因的空香港（NHK）等位基因建立了这种疾病的果蝇模型，并发现果蝇凝集素，ER降解增强α-甘露糖苷酶样蛋白2（EDEM 2），可以加速A1 AT的降解。NHK是一种罕见的等位基因，在这项研究中，我们深入研究了果蝇EDEM影响Z变体降解的机制，Z变体是主要的疾病等位基因。具体来说，我们报告说，Z等位基因不激活ER应激信号作为显着的NHK等位基因，但同样需要果蝇EDEM 1和EDEM 2的蛋白质的降解。我们证明了EDEM是其泛素化所必需的，没有EDEM，糖基化A1 AT突变体在细胞中积累。这些结果支持了EDEM介导的α-1-抗胰蛋白酶Z（ATZ）等位基因泛素化的作用，并建立了一个研究这种蛋白质和疾病的果蝇模型。
The synthesis of proteins in the endoplasmic reticulum (ER) that exceeds the protein folding capacity of this organelle is a frequent cause of cellular dysfunction and disease. An example of such a disease is alpha-1-antitrypsin (A1AT) deficiency, caused by destabilizing mutations in this glycoprotein. It is considered that the mutant proteins are recognized in the ER by lectins and are subsequently degraded through the proteasome, leading to a deficiency in this enzyme in the afflicted patients. We previously established a Drosophila model of this disease by overexpressing the null Hong Kong (NHK) allele of this gene and found that the Drosophila lectin, ER degradation-enhancing α-mannosidase-like protein 2 (EDEM2), can accelerate the degradation of A1AT when overexpressed. NHK is a rare allele, and in this study, we investigated in depth the mechanisms through which Drosophila EDEMs affect the degradation of the Z variant, which is the predominant disease allele. Specifically, we report that the Z allele does not activate ER stress signaling as prominently as the NHK allele, but similarly requires both Drosophila EDEM1 and EDEM2 for the degradation of the protein. We demonstrate that EDEMs are required for their ubiquitination, and without EDEMs, glycosylated A1AT mutants accumulate in cells. These results support the role of the EDEM-mediated ubiquitination of the alpha-1-antitrypsin Z (ATZ) allele, and establish a Drosophila model for the study of this protein and disease.
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影响因子：
64.8
作者：
LOMAS, DA;EVANS, DL;CARRELL, RW
通讯作者：
CARRELL, RW
影响因子：
4.8
作者：
Liu, Y;Choudhury, P;Sifers, RN
通讯作者：
Sifers, RN
影响因子：
4.8
作者：
Kroeger, Heike;Miranda, Elena;Lomas, David A.
通讯作者：
Lomas, David A.
影响因子：
4.8
作者：
Lin, L;Schmidt, B;Perlmutter, DH
通讯作者：
Perlmutter, DH
DOI：
10.1152/ajpgi.2000.278.1.g39
发表时间：
2000-01-01
影响因子：
4.5
作者：
Teckman, JH;Gilmore, R;Perlmutter, DH
通讯作者：
Perlmutter, DH