Cholesterol regulates Syntaxin 6 trafficking at trans-Golgi network endosomal boundaries
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.
|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.;|
|Publisher Name||Cell Reports|
|URL link to publisher's version||http://www.ncbi.nlm.nih.gov/pubmed/24746815|
|OpenAccess link to author's accepted manuscript version||https://publications.gimr.garvan.org.au/open-access/12426|