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Title: Cholesterol transport from late endosomes to the Golgi regulates t-SNARE trafficking, assembly, and function
Author: Reverter Martín, Meritxell
Rentero Alfonso, Carles
Vilà de Muga, Sandra
Alvarez-Guaita, Anna
Mulay, Vishwaroop
Wood, Peta
Monastyrskaya, Katia
Pol i Sorolla, Albert
Tebar Ramon, Francesc
Blasi Cabús, Joan
Grewal, Thomas
Enrich Bastús, Carles
Cairns, Rose
Keywords: Colesterol
Transport biològic
Biologia molecular
Aparell de Golgi
Biological transport
Molecular biology
Golgi apparatus
Issue Date: 1-Nov-2011
Publisher: American Society for Cell Biology
Abstract: Cholesterol regulates plasma membrane (PM) association and functioning of syntaxin-4 and soluble N-ethylmaleimide-sensitive fusion protein 23 (SNAP23) in the secretory pathway. However, the molecular mechanism and cellular cholesterol pools that determine the localization and assembly of these target membrane SNAP receptors (t-SNAREs) are largely unknown. We recently demonstrated that high levels of annexin A6 (AnxA6) induce accumulation of cholesterol in late endosomes, thereby reducing cholesterol in the Golgi and PM. This leads to an impaired supply of cholesterol needed for cytosolic phospholipase A2 (cPLA2) to drive Golgi vesiculation and caveolin transport to the cell surface. Using AnxA6-overexpressing cells as a model for cellular cholesterol imbalance, we identify impaired cholesterol egress from late endosomes and diminution of Golgi cholesterol as correlating with the sequestration of SNAP23/syntaxin-4 in Golgi membranes. Pharmacological accumulation of late endosomal cholesterol and cPLA2 inhibition induces a similar phenotype in control cells with low AnxA6 levels. Ectopic expression of Niemann-Pick C1 (NPC1) or exogenous cholesterol restores the location of SNAP23 and syntaxin-4 within the PM. Importantly, AnxA6-mediated mislocalization of these t-SNAREs correlates with reduced secretion of cargo via the SNAP23/syntaxin-4¿dependent constitutive exocytic pathway. We thus conclude that inhibition of late endosomal export and Golgi cholesterol depletion modulate t-SNARE localization and functioning along the exocytic pathway.
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It is part of: Molecular Biology of the Cell, 2011, vol. 22, núm 21, p. 4108-4123
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ISSN: 1059-1524
Appears in Collections:Articles publicats en revistes (Patologia i Terapèutica Experimental)
Articles publicats en revistes (Biomedicina)
Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))

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