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Vacuolization of mucolipidosis type II mouse exocrine gland cells represents accumulation of autolysosomes

We previously reported that mice deficient in UDP-GlcNAc:lysosomal enzyme GlcNAc-1-phosphotransferase (mucolipidosis type II or Gnptab −/− mice), the enzyme that initiates the addition of the mannose 6-phosphate lysosomal sorting signal on acid hydrolases, exhibited extensive vacuolization of their...

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Autores principales: Boonen, Marielle, van Meel, Eline, Oorschot, Viola, Klumperman, Judith, Kornfeld, Stuart
Formato: Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3078071/
https://www.ncbi.nlm.nih.gov/pubmed/21325625
http://dx.doi.org/10.1091/mbc.E10-07-0584
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author Boonen, Marielle
van Meel, Eline
Oorschot, Viola
Klumperman, Judith
Kornfeld, Stuart
author_facet Boonen, Marielle
van Meel, Eline
Oorschot, Viola
Klumperman, Judith
Kornfeld, Stuart
author_sort Boonen, Marielle
collection PubMed
description We previously reported that mice deficient in UDP-GlcNAc:lysosomal enzyme GlcNAc-1-phosphotransferase (mucolipidosis type II or Gnptab −/− mice), the enzyme that initiates the addition of the mannose 6-phosphate lysosomal sorting signal on acid hydrolases, exhibited extensive vacuolization of their exocrine gland cells, while the liver, brain, and muscle appeared grossly unaffected. Similar pathological findings were observed in several exocrine glands of patients with mucolipidosis II. To understand the basis for this cell type–specific abnormality, we analyzed these tissues in Gnptab −/− mice using a combined immunoelectron microscopy and biochemical approach. We demonstrate that the vacuoles in the exocrine glands are enlarged autolysosomes containing undigested cytoplasmic material that accumulate secondary to deficient lysosomal function. Surprisingly, the acid hydrolase levels in these tissues ranged from normal to modestly decreased, in contrast to skin fibroblasts, which accumulate enlarged lysosomes and/or autolysosomes also but exhibit very low levels of acid hydrolases. We propose that the lysosomal defect in the exocrine cells is caused by the combination of increased secretion of the acid hydrolases via the constitutive pathway along with their entrapment in secretory granules. Taken together, our results provide new insights into the mechanisms of the tissue-specific abnormalities seen in mucolipidosis type II.
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spelling pubmed-30780712011-06-30 Vacuolization of mucolipidosis type II mouse exocrine gland cells represents accumulation of autolysosomes Boonen, Marielle van Meel, Eline Oorschot, Viola Klumperman, Judith Kornfeld, Stuart Mol Biol Cell Articles We previously reported that mice deficient in UDP-GlcNAc:lysosomal enzyme GlcNAc-1-phosphotransferase (mucolipidosis type II or Gnptab −/− mice), the enzyme that initiates the addition of the mannose 6-phosphate lysosomal sorting signal on acid hydrolases, exhibited extensive vacuolization of their exocrine gland cells, while the liver, brain, and muscle appeared grossly unaffected. Similar pathological findings were observed in several exocrine glands of patients with mucolipidosis II. To understand the basis for this cell type–specific abnormality, we analyzed these tissues in Gnptab −/− mice using a combined immunoelectron microscopy and biochemical approach. We demonstrate that the vacuoles in the exocrine glands are enlarged autolysosomes containing undigested cytoplasmic material that accumulate secondary to deficient lysosomal function. Surprisingly, the acid hydrolase levels in these tissues ranged from normal to modestly decreased, in contrast to skin fibroblasts, which accumulate enlarged lysosomes and/or autolysosomes also but exhibit very low levels of acid hydrolases. We propose that the lysosomal defect in the exocrine cells is caused by the combination of increased secretion of the acid hydrolases via the constitutive pathway along with their entrapment in secretory granules. Taken together, our results provide new insights into the mechanisms of the tissue-specific abnormalities seen in mucolipidosis type II. The American Society for Cell Biology 2011-04-15 /pmc/articles/PMC3078071/ /pubmed/21325625 http://dx.doi.org/10.1091/mbc.E10-07-0584 Text en © 2011 Boonen 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
Boonen, Marielle
van Meel, Eline
Oorschot, Viola
Klumperman, Judith
Kornfeld, Stuart
Vacuolization of mucolipidosis type II mouse exocrine gland cells represents accumulation of autolysosomes
title Vacuolization of mucolipidosis type II mouse exocrine gland cells represents accumulation of autolysosomes
title_full Vacuolization of mucolipidosis type II mouse exocrine gland cells represents accumulation of autolysosomes
title_fullStr Vacuolization of mucolipidosis type II mouse exocrine gland cells represents accumulation of autolysosomes
title_full_unstemmed Vacuolization of mucolipidosis type II mouse exocrine gland cells represents accumulation of autolysosomes
title_short Vacuolization of mucolipidosis type II mouse exocrine gland cells represents accumulation of autolysosomes
title_sort vacuolization of mucolipidosis type ii mouse exocrine gland cells represents accumulation of autolysosomes
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3078071/
https://www.ncbi.nlm.nih.gov/pubmed/21325625
http://dx.doi.org/10.1091/mbc.E10-07-0584
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