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Mutation of SIMPLE in Charcot–Marie–Tooth 1C alters production of exosomes
Charcot–Marie–Tooth (CMT) disease is an inherited neurological disorder. Mutations in the small integral membrane protein of the lysosome/late endosome (SIMPLE) account for the rare autosomal-dominant demyelination in CMT1C patients. Understanding the molecular basis of CMT1C pathogenesis is impeded...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The American Society for Cell Biology
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3667717/ https://www.ncbi.nlm.nih.gov/pubmed/23576546 http://dx.doi.org/10.1091/mbc.E12-07-0544 |
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author | Zhu, Hong Guariglia, Sara Yu, Raymond Y. L. Li, Wenjing Brancho, Deborah Peinado, Hector Lyden, David Salzer, James Bennett, Craig Chow, Chi-Wing |
author_facet | Zhu, Hong Guariglia, Sara Yu, Raymond Y. L. Li, Wenjing Brancho, Deborah Peinado, Hector Lyden, David Salzer, James Bennett, Craig Chow, Chi-Wing |
author_sort | Zhu, Hong |
collection | PubMed |
description | Charcot–Marie–Tooth (CMT) disease is an inherited neurological disorder. Mutations in the small integral membrane protein of the lysosome/late endosome (SIMPLE) account for the rare autosomal-dominant demyelination in CMT1C patients. Understanding the molecular basis of CMT1C pathogenesis is impeded, in part, by perplexity about the role of SIMPLE, which is expressed in multiple cell types. Here we show that SIMPLE resides within the intraluminal vesicles of multivesicular bodies (MVBs) and inside exosomes, which are nanovesicles secreted extracellularly. Targeting of SIMPLE to exosomes is modulated by positive and negative regulatory motifs. We also find that expression of SIMPLE increases the number of exosomes and secretion of exosome proteins. We engineer a point mutation on the SIMPLE allele and generate a physiological mouse model that expresses CMT1C-mutated SIMPLE at the endogenous level. We find that CMT1C mouse primary embryonic fibroblasts show decreased number of exosomes and reduced secretion of exosome proteins, in part due to improper formation of MVBs. CMT1C patient B cells and CMT1C mouse primary Schwann cells show similar defects. Together the data indicate that SIMPLE regulates the production of exosomes by modulating the formation of MVBs. Dysregulated endosomal trafficking and changes in the landscape of exosome-mediated intercellular communications may place an overwhelming burden on the nervous system and account for CMT1C molecular pathogenesis. |
format | Online Article Text |
id | pubmed-3667717 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | The American Society for Cell Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-36677172013-08-16 Mutation of SIMPLE in Charcot–Marie–Tooth 1C alters production of exosomes Zhu, Hong Guariglia, Sara Yu, Raymond Y. L. Li, Wenjing Brancho, Deborah Peinado, Hector Lyden, David Salzer, James Bennett, Craig Chow, Chi-Wing Mol Biol Cell Articles Charcot–Marie–Tooth (CMT) disease is an inherited neurological disorder. Mutations in the small integral membrane protein of the lysosome/late endosome (SIMPLE) account for the rare autosomal-dominant demyelination in CMT1C patients. Understanding the molecular basis of CMT1C pathogenesis is impeded, in part, by perplexity about the role of SIMPLE, which is expressed in multiple cell types. Here we show that SIMPLE resides within the intraluminal vesicles of multivesicular bodies (MVBs) and inside exosomes, which are nanovesicles secreted extracellularly. Targeting of SIMPLE to exosomes is modulated by positive and negative regulatory motifs. We also find that expression of SIMPLE increases the number of exosomes and secretion of exosome proteins. We engineer a point mutation on the SIMPLE allele and generate a physiological mouse model that expresses CMT1C-mutated SIMPLE at the endogenous level. We find that CMT1C mouse primary embryonic fibroblasts show decreased number of exosomes and reduced secretion of exosome proteins, in part due to improper formation of MVBs. CMT1C patient B cells and CMT1C mouse primary Schwann cells show similar defects. Together the data indicate that SIMPLE regulates the production of exosomes by modulating the formation of MVBs. Dysregulated endosomal trafficking and changes in the landscape of exosome-mediated intercellular communications may place an overwhelming burden on the nervous system and account for CMT1C molecular pathogenesis. The American Society for Cell Biology 2013-06-01 /pmc/articles/PMC3667717/ /pubmed/23576546 http://dx.doi.org/10.1091/mbc.E12-07-0544 Text en © 2013 Zhu et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society of Cell Biology. |
spellingShingle | Articles Zhu, Hong Guariglia, Sara Yu, Raymond Y. L. Li, Wenjing Brancho, Deborah Peinado, Hector Lyden, David Salzer, James Bennett, Craig Chow, Chi-Wing Mutation of SIMPLE in Charcot–Marie–Tooth 1C alters production of exosomes |
title | Mutation of SIMPLE in Charcot–Marie–Tooth 1C alters production of exosomes |
title_full | Mutation of SIMPLE in Charcot–Marie–Tooth 1C alters production of exosomes |
title_fullStr | Mutation of SIMPLE in Charcot–Marie–Tooth 1C alters production of exosomes |
title_full_unstemmed | Mutation of SIMPLE in Charcot–Marie–Tooth 1C alters production of exosomes |
title_short | Mutation of SIMPLE in Charcot–Marie–Tooth 1C alters production of exosomes |
title_sort | mutation of simple in charcot–marie–tooth 1c alters production of exosomes |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3667717/ https://www.ncbi.nlm.nih.gov/pubmed/23576546 http://dx.doi.org/10.1091/mbc.E12-07-0544 |
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