Upregulation of Sortilin, a Lysosomal Sorting Receptor, Corresponds with Reduced Bioavailability of Latent TGFβ in Mucolipidosis II Cells
Mucolipidosis II (ML-II) is a lysosomal disease caused by defects in the carbohydrate-dependent sorting of soluble hydrolases to lysosomes. Altered growth factor signaling has been identified as a contributor to the phenotypes associated with ML-II and other lysosomal disorders but an understanding...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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MDPI
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7277838/ https://www.ncbi.nlm.nih.gov/pubmed/32357547 http://dx.doi.org/10.3390/biom10050670 |
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author | Barnes, Jarrod W. Aarnio-Peterson, Megan Norris, Joy Haskins, Mark Flanagan-Steet, Heather Steet, Richard |
author_facet | Barnes, Jarrod W. Aarnio-Peterson, Megan Norris, Joy Haskins, Mark Flanagan-Steet, Heather Steet, Richard |
author_sort | Barnes, Jarrod W. |
collection | PubMed |
description | Mucolipidosis II (ML-II) is a lysosomal disease caused by defects in the carbohydrate-dependent sorting of soluble hydrolases to lysosomes. Altered growth factor signaling has been identified as a contributor to the phenotypes associated with ML-II and other lysosomal disorders but an understanding of how these signaling pathways are affected is still emerging. Here, we investigated transforming growth factor beta 1 (TGFβ1) signaling in the context of ML-II patient fibroblasts, observing decreased TGFβ1 signaling that was accompanied by impaired TGFβ1-dependent wound closure. We found increased intracellular latent TGFβ1 complexes, caused by reduced secretion and stable localization in detergent-resistant lysosomes. Sortilin, a sorting receptor for hydrolases and TGFβ-related cytokines, was upregulated in ML-II fibroblasts as well as GNPTAB-null HeLa cells, suggesting a mechanism for inappropriate lysosomal targeting of TGFβ. Co-expression of sortilin and TGFβ in HeLa cells resulted in reduced TGFβ1 secretion. Elevated sortilin levels correlated with normal levels of cathepsin D in ML-II cells, consistent with a compensatory role for this receptor in lysosomal hydrolase targeting. Collectively, these data support a model whereby sortilin upregulation in cells with lysosomal storage maintains hydrolase sorting but suppresses TGFβ1 secretion through increased lysosomal delivery. These findings highlight an unexpected link between impaired lysosomal sorting and altered growth factor bioavailability. |
format | Online Article Text |
id | pubmed-7277838 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-72778382020-06-12 Upregulation of Sortilin, a Lysosomal Sorting Receptor, Corresponds with Reduced Bioavailability of Latent TGFβ in Mucolipidosis II Cells Barnes, Jarrod W. Aarnio-Peterson, Megan Norris, Joy Haskins, Mark Flanagan-Steet, Heather Steet, Richard Biomolecules Article Mucolipidosis II (ML-II) is a lysosomal disease caused by defects in the carbohydrate-dependent sorting of soluble hydrolases to lysosomes. Altered growth factor signaling has been identified as a contributor to the phenotypes associated with ML-II and other lysosomal disorders but an understanding of how these signaling pathways are affected is still emerging. Here, we investigated transforming growth factor beta 1 (TGFβ1) signaling in the context of ML-II patient fibroblasts, observing decreased TGFβ1 signaling that was accompanied by impaired TGFβ1-dependent wound closure. We found increased intracellular latent TGFβ1 complexes, caused by reduced secretion and stable localization in detergent-resistant lysosomes. Sortilin, a sorting receptor for hydrolases and TGFβ-related cytokines, was upregulated in ML-II fibroblasts as well as GNPTAB-null HeLa cells, suggesting a mechanism for inappropriate lysosomal targeting of TGFβ. Co-expression of sortilin and TGFβ in HeLa cells resulted in reduced TGFβ1 secretion. Elevated sortilin levels correlated with normal levels of cathepsin D in ML-II cells, consistent with a compensatory role for this receptor in lysosomal hydrolase targeting. Collectively, these data support a model whereby sortilin upregulation in cells with lysosomal storage maintains hydrolase sorting but suppresses TGFβ1 secretion through increased lysosomal delivery. These findings highlight an unexpected link between impaired lysosomal sorting and altered growth factor bioavailability. MDPI 2020-04-26 /pmc/articles/PMC7277838/ /pubmed/32357547 http://dx.doi.org/10.3390/biom10050670 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Barnes, Jarrod W. Aarnio-Peterson, Megan Norris, Joy Haskins, Mark Flanagan-Steet, Heather Steet, Richard Upregulation of Sortilin, a Lysosomal Sorting Receptor, Corresponds with Reduced Bioavailability of Latent TGFβ in Mucolipidosis II Cells |
title | Upregulation of Sortilin, a Lysosomal Sorting Receptor, Corresponds with Reduced Bioavailability of Latent TGFβ in Mucolipidosis II Cells |
title_full | Upregulation of Sortilin, a Lysosomal Sorting Receptor, Corresponds with Reduced Bioavailability of Latent TGFβ in Mucolipidosis II Cells |
title_fullStr | Upregulation of Sortilin, a Lysosomal Sorting Receptor, Corresponds with Reduced Bioavailability of Latent TGFβ in Mucolipidosis II Cells |
title_full_unstemmed | Upregulation of Sortilin, a Lysosomal Sorting Receptor, Corresponds with Reduced Bioavailability of Latent TGFβ in Mucolipidosis II Cells |
title_short | Upregulation of Sortilin, a Lysosomal Sorting Receptor, Corresponds with Reduced Bioavailability of Latent TGFβ in Mucolipidosis II Cells |
title_sort | upregulation of sortilin, a lysosomal sorting receptor, corresponds with reduced bioavailability of latent tgfβ in mucolipidosis ii cells |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7277838/ https://www.ncbi.nlm.nih.gov/pubmed/32357547 http://dx.doi.org/10.3390/biom10050670 |
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