Annexin A6 modulates TBC1D15/Rab7/StARD3 axis to control endosomal cholesterol export in NPC1 cells
Por:
Meneses-Salas E., García-Melero A., Kanerva K., Blanco-Muñoz P., Morales-Paytuvi F., Bonjoch J., Casas J., Egert A., Beevi S.S., Jose J., Llorente-Cortés V., Rye K.-A., Heeren J., Lu A., Pol A., Tebar F., Ikonen E., Grewal T., Enrich C., Rentero C.
Publicada:
1 ene 2020
Resumen:
Cholesterol accumulation in late endosomes is a prevailing phenotype of Niemann-Pick type C1 (NPC1) mutant cells. Likewise, annexin A6 (AnxA6) overexpression induces a phenotype reminiscent of NPC1 mutant cells. Here, we demonstrate that this cellular cholesterol imbalance is due to AnxA6 promoting Rab7 inactivation via TBC1D15, a Rab7-GAP. In NPC1 mutant cells, AnxA6 depletion and eventual Rab7 activation was associated with peripheral distribution and increased mobility of late endosomes. This was accompanied by an enhanced lipid accumulation in lipid droplets in an acyl-CoA:cholesterol acyltransferase (ACAT)-dependent manner. Moreover, in AnxA6-deficient NPC1 mutant cells, Rab7-mediated rescue of late endosome-cholesterol export required the StAR-related lipid transfer domain-3 (StARD3) protein. Electron microscopy revealed a significant increase of membrane contact sites (MCS) between late endosomes and ER in NPC1 mutant cells lacking AnxA6, suggesting late endosome-cholesterol transfer to the ER via Rab7 and StARD3-dependent MCS formation. This study identifies AnxA6 as a novel gatekeeper that controls cellular distribution of late endosome-cholesterol via regulation of a Rab7-GAP and MCS formation. © 2019, The Author(s).
Filiaciones:
Meneses-Salas E.:
Departament de Biomedicina, Unitat de Biologia Cel·lular, Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona, Barcelona, 08036, Spain
Centre de Recerca Biomèdica CELLEX, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, 08036, Spain
García-Melero A.:
Departament de Biomedicina, Unitat de Biologia Cel·lular, Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona, Barcelona, 08036, Spain
Kanerva K.:
Faculty of Medicine, Anatomy, University of Helsinki, Helsinki, 00014, Finland
Minerva Foundation Institute for Medical Research, Helsinki, 00290, Finland
Blanco-Muñoz P.:
Departament de Biomedicina, Unitat de Biologia Cel·lular, Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona, Barcelona, 08036, Spain
Centre de Recerca Biomèdica CELLEX, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, 08036, Spain
Morales-Paytuvi F.:
Departament de Biomedicina, Unitat de Biologia Cel·lular, Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona, Barcelona, 08036, Spain
Centre de Recerca Biomèdica CELLEX, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, 08036, Spain
Bonjoch J.:
Departament de Biomedicina, Unitat de Biologia Cel·lular, Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona, Barcelona, 08036, Spain
Centre de Recerca Biomèdica CELLEX, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, 08036, Spain
Casas J.:
Research Unit on BioActive Molecules (RUBAM), Department of Biological Chemistry, Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), Barcelona, Spain
Egert A.:
School of Pharmacy, Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2006, Australia
Beevi S.S.:
School of Pharmacy, Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2006, Australia
Jose J.:
School of Pharmacy, Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2006, Australia
Llorente-Cortés V.:
Lipids and Cardiovascular Pathology Group, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain
CIBERCV, Institute of Health Carlos III, Madrid, Spain
Biomedical Research Institute of Barcelona-CSIC, Barcelona, Spain
Rye K.-A.:
School of Medical Sciences, University of New South Wales, Sydney, NSW 2052, Australia
Heeren J.:
Department of Biochemistry and Molecular Biology II: Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, Hamburg, 20246, Germany
Lu A.:
Department of Biochemistry, Stanford University School of Medicine, Stanford, United States
Pol A.:
Departament de Biomedicina, Unitat de Biologia Cel·lular, Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona, Barcelona, 08036, Spain
Centre de Recerca Biomèdica CELLEX, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, 08036, Spain
Institució Catalana de Recerca i Estudis Avaçats (ICREA), Barcelona, 08010, Spain
Tebar F.:
Departament de Biomedicina, Unitat de Biologia Cel·lular, Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona, Barcelona, 08036, Spain
Centre de Recerca Biomèdica CELLEX, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, 08036, Spain
Ikonen E.:
Faculty of Medicine, Anatomy, University of Helsinki, Helsinki, 00014, Finland
Minerva Foundation Institute for Medical Research, Helsinki, 00290, Finland
Grewal T.:
School of Pharmacy, Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2006, Australia
Enrich C.:
Departament de Biomedicina, Unitat de Biologia Cel·lular, Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona, Barcelona, 08036, Spain
Centre de Recerca Biomèdica CELLEX, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, 08036, Spain
Rentero C.:
Departament de Biomedicina, Unitat de Biologia Cel·lular, Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona, Barcelona, 08036, Spain
Centre de Recerca Biomèdica CELLEX, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, 08036, Spain
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