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...
| Autores: | , , , , , , , , , , , , , , , , , , , |
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| Tipo de recurso: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2020 |
| País: | España |
| Institución: | Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau) |
| Repositorio: | r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau |
| OAI Identifier: | oai:iibsantpau.fundanetsuite.com:p10191 |
| Acceso en línea: | https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=10191 https://www.scopus.com/inward/record.uri?eid=2-s2.0-85074662041&doi=10.1007%2fs00018-019-03330-y&partnerID=40&md5=dfad68f2649986defcf6cd87e0310ef6 |
| Access Level: | acceso abierto |
| Palabra clave: | calphobindin II cholesterol cholesterol acyltransferase fat droplet Rab7 protein carrier protein guanosine triphosphatase activating protein membrane protein Rab protein small interfering RNA STARD3 protein, human TBC1D15 protein, human animal cell animal tissue AnxA6 gene Article cell interaction cellular distribution controlled study electron microscopy endosome enzyme activation gene gene function gene inactivation lipid storage mouse Niemann-Pick disease cell line nonhuman protein depletion Rab7 gene StARD3 gene TBC1D15 gene animal cell membrane CHO cell line Cricetulus endoplasmic reticulum genetics human metabolism Niemann Pick disease pathology protein domain protein transport Animals Annexin A6 Carrier Proteins Cell Membrane CHO Cells Cholesterol Endoplasmic Reticulum Endosomes GTPase-Activating Proteins Humans Membrane Proteins Niemann-Pick Disease, Type C Protein D |
| 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. © 2019, The Author(s). |
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