Role of Drosophila EDEMs in the degradation of the alpha-1-antitrypsin Z variant

Jang,Bo-Yun; Ryoo,Hyung  Don; Son,Jaekyoung; Choi,Kyung-Chul; Shin,Dong-Myoung; Kang,Sang-Wook; Kang,Min-Ji

doi:10.3892/ijmm.2015.2109

Role of Drosophila EDEMs in the degradation of the alpha-1-antitrypsin Z variant

Authors:
- Bo-Yun Jang
- Hyung Don Ryoo
- Jaekyoung Son
- Kyung-Chul Choi
- Dong-Myoung Shin
- Sang-Wook Kang
- Min-Ji Kang
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Affiliations: Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea, Department of Cell Biology, New York University School of Medicine, New York, NY 10016, USA
Published online on: February 25, 2015 https://doi.org/10.3892/ijmm.2015.2109
Pages: 870-876
Copyright: © Jang et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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Abstract

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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