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Title: Annexin A6 modulates TBC1D15/Rab7/StARD3 axis to control endosomal cholesterol export in NPC1 cells
Author: Meneses Salas, Elsa
García Melero, Ana
Kanerva, Kristiina
Blanco Muñoz, Patricia
Morales Paytuvi, Frederic
Bonjoch, Júlia
Casas Brugulat, Josefina
Egert, Antonia
Beevi, Syed S.
Jose, Jaimy
Llorente Cortés, Vicenta
Rye, Kerry-Anne
Heeren, Joerg
Lu, Albert
Pol i Sorolla, Albert
Tebar Ramon, Francesc
Ikonen, Elina
Grewal, Thomas
Enrich Bastús, Carles
Rentero Alfonso, Carles
Keywords: Colesterol
Proteïnes de membrana
Membrane proteins
Issue Date: 29-Oct-2019
Publisher: Springer Verlag
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.
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It is part of: Cellular and Molecular Life Sciences, 2019
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ISSN: 1420-682X
Appears in Collections:Articles publicats en revistes (Biomedicina)
Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer)

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