Annexin A6 modulates TBC1D15/Rab7/StARD3 axis to control endosomal cholesterol export in NPC1 cells
Meneses-Salas, Elsa (Centre de Recerca Biomèdica CELLEX)
García-Melero, Ana (Universitat de Barcelona)
Kanerva, Kristiina (Minerva Foundation Institute for Medical Research)
Blanco-Muñoz, Patricia (Centre de Recerca Biomèdica CELLEX)
Morales-Paytuvi, Frederic (Centre de Recerca Biomèdica CELLEX)
Bonjoch, Júlia (Centre de Recerca Biomèdica CELLEX)
Casas, Josefina (Institut de Química Avançada de Catalunya)
Egert, Antonia (University of Sydney)
Beevi, Syed S. (University of Sydney)
Jose, Jaimy (University of Sydney)
Llorente-Cortes, Vicenta (Institut d'Investigació Biomèdica Sant Pau)
Rye, Kerry-Anne (University of New South Wales)
Heeren, Joerg (University Medical Center Hamburg-Eppendorf)
Lu, Albert (Stanford University School of Medicine)
Pol, Albert (Institució Catalana de Recerca i Estudis Avançats)
Tebar, Francesc (Centre de Recerca Biomèdica CELLEX)
Ikonen, Elina (Minerva Foundation Institute for Medical Research)
Grewal, Thomas (University of Sydney)
Enrich, Carlos (Centre de Recerca Biomèdica CELLEX)
Rentero, Carles (Centre de Recerca Biomèdica CELLEX)
Universitat Autònoma de Barcelona

Date:	2020
Abstract:	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.
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Annexin A6 ; Cholesterol ; Late endosomes ; Membrane contact sites ; NPC1 ; Rab7
Published in:	Cellular and molecular life sciences, Vol. 77 Núm. 14 (january 2020) , p. 2839-2857, ISSN 1420-9071

DOI: 10.1007/s00018-019-03330-y
PMID: 31664461

19 p, 11.0 MB

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Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut de Recerca Sant Pau
Articles > Research articles
Articles > Published articles