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Pdro, a protein associated with late endosomes and lysosomes and implicated in cellular cholesterol homeostasis.
Guillaumot P., Luquain C., Malek M., Huber A.-L., Brugière S., Garin J., Grunwald D., Régnier D., Pétrilli V., Lefai E. et al
PLoS ONE 5, 6 (2010) e10977 - http://www.hal.inserm.fr/inserm-00763417
Pdro, a protein associated with late endosomes and lysosomes and implicated in cellular cholesterol homeostasis.
Patricia Guillaumot1, Céline Luquain2, Mouhannad Malek1, Anne-Laure Huber1, Sabine Brugière3, Jérome Garin3, Didier Grunwald4, Daniel Régnier1, Virginie Pétrilli1, Etienne Lefai2, Serge Manié () 1
1 :  GMSC - Génétique moléculaire, signalisation et cancer
CNRS : UMR5201 – Université Claude Bernard - Lyon I
niv. 3 - esc. B 8 Avenue Rockefeller 69373 LYON CEDEX 08
2 :  Régulations métaboliques, nutrition et diabètes
INSERM : U870 – Hospices Civils de Lyon – Université Claude Bernard - Lyon I – Institut National des Sciences Appliquées [INSA] - Lyon – Institut national de la recherche agronomique (INRA) : UMR1235
faculte de medecine lyon-rth laennec 7, rue guillaume paradin 69372 Lyon cedex 08
3 :  Laboratoire de chimie des protéines
INSERM : ERM0201 – CEA : DSV/IRTSV – Université Joseph Fourier - Grenoble I
4 :  Transduction du signal : signalisation calcium, phosphorylation et inflammation
INSERM : U873 – CEA : DSV/IRTSV – Université Joseph Fourier - Grenoble I
CEA 17, rue des martyrs IRTSV - LTS 38054 GRENOBLE CEDEX 9
ANTE-INSERM U836, équipe 4, Muscles et pathologies
BACKGROUND: Cellular cholesterol is a vital component of the cell membrane. Its concentration is tightly controlled by mechanisms that remain only partially characterized. In this study, we describe a late endosome/lysosomes-associated protein whose expression level affects cellular free cholesterol content. METHODOLOGY/PRINCIPAL FINDINGS: Using a restricted proteomic analysis of detergent-resistant membranes (DRMs), we have identified a protein encoded by gene C11orf59. It is mainly localized to late endosome/lysosome (LE/LY) compartment through N-terminal myristoylation and palmitoylation. We named it Pdro for protein associated with DRMs and endosomes. Very recently, three studies have reported on the same protein under two other names: the human p27RF-Rho that regulates RhoA activation and actin dynamics, and its rodent orthologue p18 that controls both LE/LY dynamics through the MERK-ERK pathway and the lysosomal activation of mammalian target of rapamycin complex 1 by amino acids. We found that, consistent with the presence of sterol-responsive element consensus sequences in the promoter region of C11orf59, Pdro mRNA and protein expression levels are regulated positively by cellular cholesterol depletion and negatively by cellular cholesterol loading. Conversely, Pdro is involved in the regulation of cholesterol homeostasis, since its depletion by siRNA increases cellular free cholesterol content that is accompanied by an increased cholesterol efflux from cells. On the other hand, cells stably overexpressing Pdro display reduced cellular free cholesterol content. Pdro depletion-mediated excess cholesterol results, at least in part, from a stimulated low-density lipoprotein (LDL) uptake and an increased cholesterol egress from LE/LY. CONCLUSIONS/SIGNIFICANCE: LDL-derived cholesterol release involves LE/LY motility that is linked to actin dynamics. Because Pdro regulates these two processes, we propose that modulation of Pdro expression in response to sterol levels regulates LDL-derived cholesterol through both LDL uptake and LE/LY dynamics, to ultimately control free cholesterol homeostasis.
Sciences du Vivant/Biologie cellulaire

Articles dans des revues avec comité de lecture
Publisher Public Library of Science
ISSN 1932-6203 

Amino Acid Sequence – Base Sequence – Biological Transport – Carrier Proteins – Cholesterol – DNA Primers – Endosomes – Flow Cytometry – Fluorescent Antibody Technique – Gene Knockdown Techniques – Homeostasis – Humans – Lipoproteins – LDL – Lysosomes – Molecular Sequence Data – Reverse Transcriptase Polymerase Chain Reaction – Tandem Mass Spectrometry – Amino Acid Sequence
This work was supported by institutional grants from CNRS and additional support from Association pour la Recherche contre le Cancer (ARC: SM 3811 and 4915), Fondation De France (FDF: 2002 010 893) and Ligue Nationale Contre le Cancer Comite du Rhone. CL was supported by fellowships from FDF.
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