Annexin A6 modulates TBC1D15/Rab7/StARD3 axis to control endosomal cholesterol export in NPC1 cells

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...

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Detalles Bibliográficos
Autores: Meneses-Salas, Elsa, García-Melero, Ana, Kanerva, Kristiina, Blanco-Muñoz, Patricia, Morales-Paytuvi, Frederic, Bonjoch, Júlia, Casas, Josefina, Egert, Antonia, Beevi, Syed S., Jose, Jaimy, Llorente-Cortés, Vicenta, Rye, Kerry-Anne, Heeren, Joerg, Lu, Albert, Pol, Albert, Tebar, Francesc, Ikonen, Elina, Grewal, Thomas, Enrich, Carlos, Rentero, Carles
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2019
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/200681
Acceso en línea:http://hdl.handle.net/10261/200681
Access Level:acceso abierto
Palabra clave:Membranes
Endoplasmic Reticulum
Sites MCSs
Cholesterol
Late endosomes
Rab7
NPC1
Annexin A6
Membrane contact sites
Descripción
Sumario: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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