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Modulation of PICALM Levels Perturbs Cellular Cholesterol Homeostasis

PICALM (Phosphatidyl Inositol Clathrin Assembly Lymphoid Myeloid protein) is a ubiquitously expressed protein that plays a role in clathrin-mediated endocytosis. PICALM also affects the internalization and trafficking of SNAREs and modulates macroautophagy. Chromosomal translocations that result in...

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Autores principales: Mercer, Jacob L., Argus, Joseph P., Crabtree, Donna M., Keenan, Melissa M., Wilks, Moses Q., Chi, Jen-Tsan Ashley, Bensinger, Steven J., Lavau, Catherine P., Wechsler, Daniel S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4467867/
https://www.ncbi.nlm.nih.gov/pubmed/26075887
http://dx.doi.org/10.1371/journal.pone.0129776
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author Mercer, Jacob L.
Argus, Joseph P.
Crabtree, Donna M.
Keenan, Melissa M.
Wilks, Moses Q.
Chi, Jen-Tsan Ashley
Bensinger, Steven J.
Lavau, Catherine P.
Wechsler, Daniel S.
author_facet Mercer, Jacob L.
Argus, Joseph P.
Crabtree, Donna M.
Keenan, Melissa M.
Wilks, Moses Q.
Chi, Jen-Tsan Ashley
Bensinger, Steven J.
Lavau, Catherine P.
Wechsler, Daniel S.
author_sort Mercer, Jacob L.
collection PubMed
description PICALM (Phosphatidyl Inositol Clathrin Assembly Lymphoid Myeloid protein) is a ubiquitously expressed protein that plays a role in clathrin-mediated endocytosis. PICALM also affects the internalization and trafficking of SNAREs and modulates macroautophagy. Chromosomal translocations that result in the fusion of PICALM to heterologous proteins cause leukemias, and genome-wide association studies have linked PICALM Single Nucleotide Polymorphisms (SNPs) to Alzheimer’s disease. To obtain insight into the biological role of PICALM, we performed gene expression studies of PICALM-deficient and PICALM-expressing cells. Pathway analysis demonstrated that PICALM expression influences the expression of genes that encode proteins involved in cholesterol biosynthesis and lipoprotein uptake. Gas Chromatography-Mass Spectrometry (GC-MS) studies indicated that loss of PICALM increases cellular cholesterol pool size. Isotopic labeling studies revealed that loss of PICALM alters increased net scavenging of cholesterol. Flow cytometry analyses confirmed that internalization of the LDL receptor is enhanced in PICALM-deficient cells as a result of higher levels of LDLR expression. These findings suggest that PICALM is required for cellular cholesterol homeostasis and point to a novel mechanism by which PICALM alterations may contribute to disease.
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spelling pubmed-44678672015-06-25 Modulation of PICALM Levels Perturbs Cellular Cholesterol Homeostasis Mercer, Jacob L. Argus, Joseph P. Crabtree, Donna M. Keenan, Melissa M. Wilks, Moses Q. Chi, Jen-Tsan Ashley Bensinger, Steven J. Lavau, Catherine P. Wechsler, Daniel S. PLoS One Research Article PICALM (Phosphatidyl Inositol Clathrin Assembly Lymphoid Myeloid protein) is a ubiquitously expressed protein that plays a role in clathrin-mediated endocytosis. PICALM also affects the internalization and trafficking of SNAREs and modulates macroautophagy. Chromosomal translocations that result in the fusion of PICALM to heterologous proteins cause leukemias, and genome-wide association studies have linked PICALM Single Nucleotide Polymorphisms (SNPs) to Alzheimer’s disease. To obtain insight into the biological role of PICALM, we performed gene expression studies of PICALM-deficient and PICALM-expressing cells. Pathway analysis demonstrated that PICALM expression influences the expression of genes that encode proteins involved in cholesterol biosynthesis and lipoprotein uptake. Gas Chromatography-Mass Spectrometry (GC-MS) studies indicated that loss of PICALM increases cellular cholesterol pool size. Isotopic labeling studies revealed that loss of PICALM alters increased net scavenging of cholesterol. Flow cytometry analyses confirmed that internalization of the LDL receptor is enhanced in PICALM-deficient cells as a result of higher levels of LDLR expression. These findings suggest that PICALM is required for cellular cholesterol homeostasis and point to a novel mechanism by which PICALM alterations may contribute to disease. Public Library of Science 2015-06-15 /pmc/articles/PMC4467867/ /pubmed/26075887 http://dx.doi.org/10.1371/journal.pone.0129776 Text en © 2015 Mercer et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Mercer, Jacob L.
Argus, Joseph P.
Crabtree, Donna M.
Keenan, Melissa M.
Wilks, Moses Q.
Chi, Jen-Tsan Ashley
Bensinger, Steven J.
Lavau, Catherine P.
Wechsler, Daniel S.
Modulation of PICALM Levels Perturbs Cellular Cholesterol Homeostasis
title Modulation of PICALM Levels Perturbs Cellular Cholesterol Homeostasis
title_full Modulation of PICALM Levels Perturbs Cellular Cholesterol Homeostasis
title_fullStr Modulation of PICALM Levels Perturbs Cellular Cholesterol Homeostasis
title_full_unstemmed Modulation of PICALM Levels Perturbs Cellular Cholesterol Homeostasis
title_short Modulation of PICALM Levels Perturbs Cellular Cholesterol Homeostasis
title_sort modulation of picalm levels perturbs cellular cholesterol homeostasis
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4467867/
https://www.ncbi.nlm.nih.gov/pubmed/26075887
http://dx.doi.org/10.1371/journal.pone.0129776
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