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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

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

PMID:
24746815
DOI:
10.1016/j.celrep.2014.03.043
[Indexed for MEDLINE]
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