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

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Meneses-Salas , E , García-Melero , A , Kanerva , K , Blanco-Muñoz , P , Morales-Paytuvi , F , Bonjoch , J , Heeren , J , Lu , A , Pol , A , Tebar , F , Ikonen , E , Grewal , T , Enrich , C & Rentero , C 2020 , ' Annexin A6 modulates TBC1D15/Rab7/StARD3 axis to control endosomal cholesterol export in NPC1 cells ' , Cellular and Molecular Life Sciences , vol. 77 , no. 14 , pp. 2839-2857 . https://doi.org/10.1007/s00018-019-03330-y

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; Heeren, Joerg; Lu, Albert; Pol, Albert; Tebar, Francesc; Ikonen, Elina; Grewal, Thomas; Enrich, Carlos; Rentero, Carles
Contributor: University of Helsinki, STEMM - Stem Cells and Metabolism Research Program
University of Helsinki, STEMM - Stem Cells and Metabolism Research Program
Date: 2020-07
Language: eng
Number of pages: 19
Belongs to series: Cellular and Molecular Life Sciences
ISSN: 1420-682X
URI: http://hdl.handle.net/10138/317839
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.
Subject: 3111 Biomedicine
Cholesterol
Late endosomes
Rab7
NPC1
Annexin A6
Membrane contact sites
Cholesterol
Late endosomes
Rab7
NPC1
Annexin A6
Membrane contact sites
GTPASE-ACTIVATING PROTEIN
LOW-DENSITY-LIPOPROTEIN
MEMBRANE CONTACT SITES
LYSOSOMAL FUSION
PLASMA-MEMBRANE
TRANSPORT
ER
TRAFFICKING
BINDING
MLN64
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