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Degradation routes of trafficking-defective VLDLR mutants associated with Dysequilibrium syndrome
Low density lipoprotein receptor (LDLR) family members are involved in signaling in the developing brain. Previously we have reported that missense mutations in the Very Low Density Lipoprotein Receptor gene (VLDLR), causing Dysequilibrium syndrome (DES), disrupt ligand-binding, due to endoplasmic r...
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/PMC5785505/ https://www.ncbi.nlm.nih.gov/pubmed/29371607 http://dx.doi.org/10.1038/s41598-017-19053-8 |
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author | Kizhakkedath, Praseetha John, Anne Al-Gazali, Lihadh Ali, Bassam R. |
author_facet | Kizhakkedath, Praseetha John, Anne Al-Gazali, Lihadh Ali, Bassam R. |
author_sort | Kizhakkedath, Praseetha |
collection | PubMed |
description | Low density lipoprotein receptor (LDLR) family members are involved in signaling in the developing brain. Previously we have reported that missense mutations in the Very Low Density Lipoprotein Receptor gene (VLDLR), causing Dysequilibrium syndrome (DES), disrupt ligand-binding, due to endoplasmic reticulum (ER) retention of the mutants. We explored the degradation routes of these VLDLR mutants in cultured cells. Our results indicate that VLDLR mutants are retained in the ER for prolonged periods which could be facilitated by association with the ER-resident chaperone calnexin. The mutants were prone to aggregation and capable of eliciting ER stress. The VLDLR mutants were found to be degraded predominantly by the proteasomal pathway, since ubiquitinated VLDLR was found to accumulate in response to proteasomal inhibition. Further, the mutants were found to interact with the ER degradation adaptor protein SEL1L. The degradation of VLDLR wild type and mutant were delayed in CRISPR/Cas9 edited SEL1L knock-out cells which was reversed by exogenous expression of SEL1L. In summary, ER retention of pathogenic VLDLR mutants involves binding to calnexin, elevated ER stress, and delayed degradation which is dependent on SEL1L. Since core LDLR family members share common structural domains, common mechanisms may be involved in their ER processing. |
format | Online Article Text |
id | pubmed-5785505 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-57855052018-02-07 Degradation routes of trafficking-defective VLDLR mutants associated with Dysequilibrium syndrome Kizhakkedath, Praseetha John, Anne Al-Gazali, Lihadh Ali, Bassam R. Sci Rep Article Low density lipoprotein receptor (LDLR) family members are involved in signaling in the developing brain. Previously we have reported that missense mutations in the Very Low Density Lipoprotein Receptor gene (VLDLR), causing Dysequilibrium syndrome (DES), disrupt ligand-binding, due to endoplasmic reticulum (ER) retention of the mutants. We explored the degradation routes of these VLDLR mutants in cultured cells. Our results indicate that VLDLR mutants are retained in the ER for prolonged periods which could be facilitated by association with the ER-resident chaperone calnexin. The mutants were prone to aggregation and capable of eliciting ER stress. The VLDLR mutants were found to be degraded predominantly by the proteasomal pathway, since ubiquitinated VLDLR was found to accumulate in response to proteasomal inhibition. Further, the mutants were found to interact with the ER degradation adaptor protein SEL1L. The degradation of VLDLR wild type and mutant were delayed in CRISPR/Cas9 edited SEL1L knock-out cells which was reversed by exogenous expression of SEL1L. In summary, ER retention of pathogenic VLDLR mutants involves binding to calnexin, elevated ER stress, and delayed degradation which is dependent on SEL1L. Since core LDLR family members share common structural domains, common mechanisms may be involved in their ER processing. Nature Publishing Group UK 2018-01-25 /pmc/articles/PMC5785505/ /pubmed/29371607 http://dx.doi.org/10.1038/s41598-017-19053-8 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 Kizhakkedath, Praseetha John, Anne Al-Gazali, Lihadh Ali, Bassam R. Degradation routes of trafficking-defective VLDLR mutants associated with Dysequilibrium syndrome |
title | Degradation routes of trafficking-defective VLDLR mutants associated with Dysequilibrium syndrome |
title_full | Degradation routes of trafficking-defective VLDLR mutants associated with Dysequilibrium syndrome |
title_fullStr | Degradation routes of trafficking-defective VLDLR mutants associated with Dysequilibrium syndrome |
title_full_unstemmed | Degradation routes of trafficking-defective VLDLR mutants associated with Dysequilibrium syndrome |
title_short | Degradation routes of trafficking-defective VLDLR mutants associated with Dysequilibrium syndrome |
title_sort | degradation routes of trafficking-defective vldlr mutants associated with dysequilibrium syndrome |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5785505/ https://www.ncbi.nlm.nih.gov/pubmed/29371607 http://dx.doi.org/10.1038/s41598-017-19053-8 |
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