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Cell Rep. 2014 May 8;7(3):883-97. doi: 10.1016/j.celrep.2014.03.043. Epub 2014 Apr 17.

Cholesterol regulates Syntaxin 6 trafficking at trans-Golgi network endosomal boundaries.

Author information

  • 1Departament de Biologia Cel·lular, Immunologia i Neurociències, Facultat de Medicina, Universitat de Barcelona, 08036 Barcelona, Spain.
  • 2Faculty of Pharmacy, University of Sydney, Sydney, NSW 2006, Australia.
  • 3Garvan Institute of Medical Research and Kinghorn Cancer Centre, Cancer Research Program, St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW 2010, Australia.
  • 4First Department of Pediatrics, University of Athens, Aghia Sofia Children's Hospital, 11527 Athens, Greece.
  • 5Departament de Genètica, Facultat de Biologia, Universitat de Barcelona, CIBERER, IBUB, 08028 Barcelona, Spain.
  • 6Centre de Recerca Biomèdica CELLEX, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain.
  • 7Department of Biochemistry and Molecular Biology II. Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
  • 8Department of Pathology and Experimental Therapeutics, IDIBELL-University of Barcelona, L'Hospitalet de Llobregat, 08907 Barcelona, Spain.
  • 9Departament de Biologia Cel·lular, Immunologia i Neurociències, Facultat de Medicina, Universitat de Barcelona, 08036 Barcelona, Spain; Centre de Recerca Biomèdica CELLEX, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; Institució Catalana de Recerca i Estudis Avaçats (ICREA), 08010 Barcelona, Spain.
  • 10Departament de Biologia Cel·lular, Immunologia i Neurociències, Facultat de Medicina, Universitat de Barcelona, 08036 Barcelona, Spain; Centre de Recerca Biomèdica CELLEX, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain.
  • 11Tissue Repair and Regeneration Program, Institute of Health and Biomedical, Innovation, Queensland University of Technology, Brisbane, QLD 4095, Australia.
  • 12Faculty of Pharmacy, University of Sydney, Sydney, NSW 2006, Australia. Electronic address: thomas.grewal@sydney.edu.au.
  • 13Departament de Biologia Cel·lular, Immunologia i Neurociències, Facultat de Medicina, Universitat de Barcelona, 08036 Barcelona, Spain; Centre de Recerca Biomèdica CELLEX, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain. Electronic address: enrich@ub.edu.

Abstract

Inhibition of cholesterol export from late endosomes causes cellular cholesterol imbalance, including cholesterol depletion in the trans-Golgi network (TGN). Here, using Chinese hamster ovary (CHO) Niemann-Pick type C1 (NPC1) mutant cell lines and human NPC1 mutant fibroblasts, we show that altered cholesterol levels at the TGN/endosome boundaries trigger Syntaxin 6 (Stx6) accumulation into VAMP3, transferrin, and Rab11-positive recycling endosomes (REs). This increases Stx6/VAMP3 interaction and interferes with the recycling of αVβ3 and α5β1 integrins and cell migration, possibly in a Stx6-dependent manner. In NPC1 mutant cells, restoration of cholesterol levels in the TGN, but not inhibition of VAMP3, restores the steady-state localization of Stx6 in the TGN. Furthermore, elevation of RE cholesterol is associated with increased amounts of Stx6 in RE. Hence, the fine-tuning of cholesterol levels at the TGN-RE boundaries together with a subset of cholesterol-sensitive SNARE proteins may play a regulatory role in cell migration and invasion.

Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

PMID:
24746815
[PubMed - indexed for MEDLINE]
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