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Dissection of the Role of VIMP in Endoplasmic Reticulum-Associated Degradation of CFTRΔF508
Endoplasmic reticulum (ER)-associated protein degradation (ERAD) is an important quality control mechanism that eliminates misfolded proteins from the ER. The Derlin-1/VCP/VIMP protein complex plays an essential role in ERAD. Although the roles of Derlin-1 and VCP are relatively clear, the functiona...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5859151/ https://www.ncbi.nlm.nih.gov/pubmed/29555962 http://dx.doi.org/10.1038/s41598-018-23284-8 |
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author | Hou, Xia Wei, Hongguang Rajagopalan, Carthic Jiang, Hong Wu, Qingtian Zaman, Khalequz Xie, Youming Sun, Fei |
author_facet | Hou, Xia Wei, Hongguang Rajagopalan, Carthic Jiang, Hong Wu, Qingtian Zaman, Khalequz Xie, Youming Sun, Fei |
author_sort | Hou, Xia |
collection | PubMed |
description | Endoplasmic reticulum (ER)-associated protein degradation (ERAD) is an important quality control mechanism that eliminates misfolded proteins from the ER. The Derlin-1/VCP/VIMP protein complex plays an essential role in ERAD. Although the roles of Derlin-1 and VCP are relatively clear, the functional activity of VIMP in ERAD remains to be understood. Here we investigate the role of VIMP in the degradation of CFTRΔF508, a cystic fibrosis transmembrane conductance regulator (CFTR) mutant known to be a substrate of ERAD. Overexpression of VIMP markedly enhances the degradation of CFTRΔF508, whereas knockdown of VIMP increases its half-life. We demonstrate that VIMP is associated with CFTRΔF508 and the RNF5 E3 ubiquitin ligase (also known as RMA1). Thus, VIMP not only forms a complex with Derlin-1 and VCP, but may also participate in recruiting substrates and E3 ubiquitin ligases. We further show that blocking CFTRΔF508 degradation by knockdown of VIMP substantially augments the effect of VX809, a drug that allows a fraction of CFTRΔF508 to fold properly and mobilize from ER to cell surface for normal functioning. This study provides insight into the role of VIMP in ERAD and presents a potential target for the treatment of cystic fibrosis patients carrying the CFTRΔF508 mutation. |
format | Online Article Text |
id | pubmed-5859151 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-58591512018-03-20 Dissection of the Role of VIMP in Endoplasmic Reticulum-Associated Degradation of CFTRΔF508 Hou, Xia Wei, Hongguang Rajagopalan, Carthic Jiang, Hong Wu, Qingtian Zaman, Khalequz Xie, Youming Sun, Fei Sci Rep Article Endoplasmic reticulum (ER)-associated protein degradation (ERAD) is an important quality control mechanism that eliminates misfolded proteins from the ER. The Derlin-1/VCP/VIMP protein complex plays an essential role in ERAD. Although the roles of Derlin-1 and VCP are relatively clear, the functional activity of VIMP in ERAD remains to be understood. Here we investigate the role of VIMP in the degradation of CFTRΔF508, a cystic fibrosis transmembrane conductance regulator (CFTR) mutant known to be a substrate of ERAD. Overexpression of VIMP markedly enhances the degradation of CFTRΔF508, whereas knockdown of VIMP increases its half-life. We demonstrate that VIMP is associated with CFTRΔF508 and the RNF5 E3 ubiquitin ligase (also known as RMA1). Thus, VIMP not only forms a complex with Derlin-1 and VCP, but may also participate in recruiting substrates and E3 ubiquitin ligases. We further show that blocking CFTRΔF508 degradation by knockdown of VIMP substantially augments the effect of VX809, a drug that allows a fraction of CFTRΔF508 to fold properly and mobilize from ER to cell surface for normal functioning. This study provides insight into the role of VIMP in ERAD and presents a potential target for the treatment of cystic fibrosis patients carrying the CFTRΔF508 mutation. Nature Publishing Group UK 2018-03-19 /pmc/articles/PMC5859151/ /pubmed/29555962 http://dx.doi.org/10.1038/s41598-018-23284-8 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Hou, Xia Wei, Hongguang Rajagopalan, Carthic Jiang, Hong Wu, Qingtian Zaman, Khalequz Xie, Youming Sun, Fei Dissection of the Role of VIMP in Endoplasmic Reticulum-Associated Degradation of CFTRΔF508 |
title | Dissection of the Role of VIMP in Endoplasmic Reticulum-Associated Degradation of CFTRΔF508 |
title_full | Dissection of the Role of VIMP in Endoplasmic Reticulum-Associated Degradation of CFTRΔF508 |
title_fullStr | Dissection of the Role of VIMP in Endoplasmic Reticulum-Associated Degradation of CFTRΔF508 |
title_full_unstemmed | Dissection of the Role of VIMP in Endoplasmic Reticulum-Associated Degradation of CFTRΔF508 |
title_short | Dissection of the Role of VIMP in Endoplasmic Reticulum-Associated Degradation of CFTRΔF508 |
title_sort | dissection of the role of vimp in endoplasmic reticulum-associated degradation of cftrδf508 |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5859151/ https://www.ncbi.nlm.nih.gov/pubmed/29555962 http://dx.doi.org/10.1038/s41598-018-23284-8 |
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