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Cholesterol transport from late endosomes to the Golgi regulates t-SNARE trafficking, assembly, and function

Reverter, Meritxell, Rentero, Carles, de Muga, Sandra Vilà, Alvarez-Guaita, Anna, Mulay, Vishwaroop, Cairns, Rose, Wood, Peta, Monastyrskaya, Katia, Pol, Albert, Tebar, Francesc, Blasi, Joan, Grewal, Thomas, Enrich, Carlos·2011·Molecular Biology of the Cell

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 A 2(cPLA 2) 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 cPLA 2 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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  • In vitro, ACAT inhibition has cell-specific effects on ABCA1 and cholesterol efflux: it increases ABCA1 levels and cholesterol efflux in cholesterol-loaded macrophages, decreases ABCA1 levels in adipocytes, and decreases ABCA1 levels, lipid catabolism, and cholesterol efflux in APOE4 microglia.

    “In vitro, ACAT inhibition increases ABCA1 levels and cholesterol efflux of cholesterol-loaded macrophages, while decreasing ABCA1 levels in adipocytes [125] and decreasing ABCA1 levels, lipid catabolism, and cholesterol efflux in APOE4 microglia [126–128]”

    From Inhibition of ACAT as a Therapeutic Target for Alzheimer's Disease Is Independent of ApoE4 Lipidation (2023) · cites this paper as [125]

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Authors
Reverter, M., Rentero, C., de Muga, S. V., Alvarez-Guaita, A., Mulay, V., Cairns, R., Wood, P., Monastyrskaya, K., Pol, A., Tebar, F., Blasi, J., Grewal, T., & Enrich, C.
Affiliations
  • Departament de Biologia Cel·lular, Immunologia i Neurociències, Facultat de Medicina, Universitat de Barcelona, 08036 Barcelona, Spain
  • Faculty of Pharmacy, University of Sydney, Sydney, NSW 2006, Australia
  • Urology Research Laboratory, Department of Clinical Research, University of Bern, 3000 Bern 9, Switzerland
  • Department of Pathology and Experimental Therapeutics, IDIBELL–University of Barcelona, 08907 L'Hospitalet de Llobregat, Barcelona, Spain
Venue
Molecular Biology of the Cell
Published
2011-11
Volume
22
Issue
21
Pages
4108-4123
ISSN
  • 1059-1524
  • 1939-4586
Cited by
69
References
0
Language
en

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