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Two phosphatidylinositol 4-kinases control lysosomal delivery of the Gaucher disease enzyme, β-glucocerebrosidase

Gaucher disease is a lysosomal storage disorder caused by a defect in the degradation of glucosylceramide catalyzed by the lysosomal enzyme β-glucocerebrosidase (GBA). GBA reaches lysosomes via association with its receptor, lysosomal integral membrane protein type 2 (LIMP-2). We found that distinct...

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Autores principales: Jović, Marko, Kean, Michelle J., Szentpetery, Zsofia, Polevoy, Gordon, Gingras, Anne-Claude, Brill, Julie A., Balla, Tamas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3327330/
https://www.ncbi.nlm.nih.gov/pubmed/22337770
http://dx.doi.org/10.1091/mbc.E11-06-0553
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author Jović, Marko
Kean, Michelle J.
Szentpetery, Zsofia
Polevoy, Gordon
Gingras, Anne-Claude
Brill, Julie A.
Balla, Tamas
author_facet Jović, Marko
Kean, Michelle J.
Szentpetery, Zsofia
Polevoy, Gordon
Gingras, Anne-Claude
Brill, Julie A.
Balla, Tamas
author_sort Jović, Marko
collection PubMed
description Gaucher disease is a lysosomal storage disorder caused by a defect in the degradation of glucosylceramide catalyzed by the lysosomal enzyme β-glucocerebrosidase (GBA). GBA reaches lysosomes via association with its receptor, lysosomal integral membrane protein type 2 (LIMP-2). We found that distinct phosphatidylinositol 4-kinases (PI4Ks) play important roles at multiple steps in the trafficking pathway of the LIMP-2/GBA complex. Acute depletion of phosphatidylinositol 4-phosphate in the Golgi caused accumulation of LIMP-2 in this compartment, and PI4KIIIβ was found to be responsible for controlling the exit of LIMP-2 from the Golgi. In contrast, depletion of PI4KIIα blocked trafficking at a post-Golgi compartment, leading to accumulation of LIMP-2 in enlarged endosomal vesicles. PI4KIIα depletion also caused secretion of missorted GBA into the medium, which was attenuated by limiting LIMP-2/GBA exit from the Golgi by PI4KIIIβ inhibitors. These studies identified PI4KIIIβ and PI4KIIα as important regulators of lysosomal delivery of GBA, revealing a new element of control to sphingolipid homeostasis by phosphoinositides.
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spelling pubmed-33273302012-06-30 Two phosphatidylinositol 4-kinases control lysosomal delivery of the Gaucher disease enzyme, β-glucocerebrosidase Jović, Marko Kean, Michelle J. Szentpetery, Zsofia Polevoy, Gordon Gingras, Anne-Claude Brill, Julie A. Balla, Tamas Mol Biol Cell Articles Gaucher disease is a lysosomal storage disorder caused by a defect in the degradation of glucosylceramide catalyzed by the lysosomal enzyme β-glucocerebrosidase (GBA). GBA reaches lysosomes via association with its receptor, lysosomal integral membrane protein type 2 (LIMP-2). We found that distinct phosphatidylinositol 4-kinases (PI4Ks) play important roles at multiple steps in the trafficking pathway of the LIMP-2/GBA complex. Acute depletion of phosphatidylinositol 4-phosphate in the Golgi caused accumulation of LIMP-2 in this compartment, and PI4KIIIβ was found to be responsible for controlling the exit of LIMP-2 from the Golgi. In contrast, depletion of PI4KIIα blocked trafficking at a post-Golgi compartment, leading to accumulation of LIMP-2 in enlarged endosomal vesicles. PI4KIIα depletion also caused secretion of missorted GBA into the medium, which was attenuated by limiting LIMP-2/GBA exit from the Golgi by PI4KIIIβ inhibitors. These studies identified PI4KIIIβ and PI4KIIα as important regulators of lysosomal delivery of GBA, revealing a new element of control to sphingolipid homeostasis by phosphoinositides. The American Society for Cell Biology 2012-04-15 /pmc/articles/PMC3327330/ /pubmed/22337770 http://dx.doi.org/10.1091/mbc.E11-06-0553 Text en © 2012 Jović 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
Jović, Marko
Kean, Michelle J.
Szentpetery, Zsofia
Polevoy, Gordon
Gingras, Anne-Claude
Brill, Julie A.
Balla, Tamas
Two phosphatidylinositol 4-kinases control lysosomal delivery of the Gaucher disease enzyme, β-glucocerebrosidase
title Two phosphatidylinositol 4-kinases control lysosomal delivery of the Gaucher disease enzyme, β-glucocerebrosidase
title_full Two phosphatidylinositol 4-kinases control lysosomal delivery of the Gaucher disease enzyme, β-glucocerebrosidase
title_fullStr Two phosphatidylinositol 4-kinases control lysosomal delivery of the Gaucher disease enzyme, β-glucocerebrosidase
title_full_unstemmed Two phosphatidylinositol 4-kinases control lysosomal delivery of the Gaucher disease enzyme, β-glucocerebrosidase
title_short Two phosphatidylinositol 4-kinases control lysosomal delivery of the Gaucher disease enzyme, β-glucocerebrosidase
title_sort two phosphatidylinositol 4-kinases control lysosomal delivery of the gaucher disease enzyme, β-glucocerebrosidase
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3327330/
https://www.ncbi.nlm.nih.gov/pubmed/22337770
http://dx.doi.org/10.1091/mbc.E11-06-0553
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