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Cholesterol transport from late endosomes to the Golgi regulates t-SNARE trafficking, assembly, and function
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
Universitat de Barcelona
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.
18-05-2012
Colesterol
Transport biològic
Biologia molecular
Aparell de Golgi
Cholesterol
Biological transport
Molecular biology
Golgi apparatus
cc-by-nc-sa, (c) Reverter et al., 2011
http://creativecommons.org/licenses/by-nc-sa/3.0/
Artículo
American Society for Cell Biology
         

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