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

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 alphaVbeta3 and alpha5beta1 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.

Type Journal
ISBN 2211-1247 (Electronic)
Authors Reverter, M.; Rentero, C.; Garcia-Melero, A.; Hoque, M.; Vila de Muga, S.; Alvarez-Guaita, A.; Conway, J. R.; Wood, P.; Cairns, R.; Lykopoulou, L.; Grinberg, D.; Vilageliu, L.; Bosch, M.; Heeren, J.; Blasi, J.; Timpson, P.; Pol, A.; Tebar, F.; Murray, R. Z.; Grewal, T.; Enrich, C.;
Garvan Authors James Conway , Dr Paul Timpson
Publisher Name Cell Reports
Published Date 2014-01-01 00:00:00
Published Volume 7
Published Issue 3
Published Pages 883-97
URL http://www.ncbi.nlm.nih.gov/pubmed/24746815
Status Published In-print
OpenAccess Link https://publications.gimr.garvan.org.au/download.php?12426_12778/1-s2.0-S221112471400240X-main.pdf