title: Pdro, a protein associated with late endosomes and lysosomes and implicated in cellular cholesterol homeostasis.
abstract: 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.
  
  
  RESULTS
  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
  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.
authors.affiliation: Génétique Moléculaire, Signalisation et Cancer, UMR 5201 CNRS, Centre Leon Berard, Lyon, France.
authors.forename: Patricia
authors.initials: P
authors.lastname: Guillaumot
authors.forename: Céline
authors.initials: C
authors.lastname: Luquain
authors.forename: Mouhannad
authors.initials: M
authors.lastname: Malek
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Huber
authors.forename: Sabine
authors.initials: S
authors.lastname: Brugière
authors.forename: Jérome
authors.initials: J
authors.lastname: Garin
authors.forename: Didier
authors.initials: D
authors.lastname: Grunwald
authors.forename: Daniel
authors.initials: D
authors.lastname: Régnier
authors.forename: Virginie
authors.initials: V
authors.lastname: Pétrilli
authors.forename: Etienne
authors.initials: E
authors.lastname: Lefai
authors.forename: Serge N
authors.initials: SN
authors.lastname: Manié
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D001692:Biological Transport; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism*; D017931:DNA Primers; D011992:Endosomes / Q000378:metabolism*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D055785:Gene Knockdown Techniques; D006706:Homeostasis; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008077:Lipoproteins, LDL / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism*; D008969:Molecular Sequence Data; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053719:Tandem Mass Spectrometry
chemical_list: D002352:Carrier Proteins; D017931:DNA Primers; D047908:Intracellular Signaling Peptides and Proteins; C544374:LAMTOR1 protein, human; D008077:Lipoproteins, LDL; D002784:Cholesterol