Annexin A6 modulates TBC1D15/Rab7/StARD3 axis to control endosomal cholesterol export in NPC1 cells.
Animals
Annexin A6
/ genetics
CHO Cells
Carrier Proteins
/ genetics
Cell Membrane
/ genetics
Cholesterol
/ genetics
Cricetulus
Endoplasmic Reticulum
/ genetics
Endosomes
/ genetics
GTPase-Activating Proteins
/ genetics
Humans
Membrane Proteins
/ genetics
Niemann-Pick Disease, Type C
/ genetics
Protein Domains
/ genetics
Protein Transport
/ genetics
RNA, Small Interfering
/ genetics
rab GTP-Binding Proteins
/ genetics
rab7 GTP-Binding Proteins
Annexin A6
Cholesterol
Late endosomes
Membrane contact sites
NPC1
Rab7
Journal
Cellular and molecular life sciences : CMLS
ISSN: 1420-9071
Titre abrégé: Cell Mol Life Sci
Pays: Switzerland
ID NLM: 9705402
Informations de publication
Date de publication:
Jul 2020
Jul 2020
Historique:
received:
16
07
2019
accepted:
01
10
2019
revised:
30
09
2019
pubmed:
31
10
2019
medline:
11
7
2020
entrez:
31
10
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31664461
doi: 10.1007/s00018-019-03330-y
pii: 10.1007/s00018-019-03330-y
pmc: PMC7326902
doi:
Substances chimiques
Annexin A6
0
Carrier Proteins
0
GTPase-Activating Proteins
0
Membrane Proteins
0
RNA, Small Interfering
0
STARD3 protein, human
0
TBC1D15 protein, human
0
rab7 GTP-Binding Proteins
0
rab7 GTP-binding proteins, human
0
Cholesterol
97C5T2UQ7J
rab GTP-Binding Proteins
EC 3.6.5.2
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
2839-2857Subventions
Organisme : Secretaría de Estado de Investigación, Desarrollo e Innovación
ID : BFU2015-66785-P
Organisme : Secretaría de Estado de Investigación, Desarrollo e Innovación
ID : CSD2009-00016
Organisme : University of Sydney
ID : U7113
Organisme : University of Sydney
ID : RY253
Organisme : University of Sydney
ID : U3367
Organisme : Academy of Findland
ID : 282192
Organisme : Academy of Finland
ID : 307415
Organisme : Academy of Finland
ID : 312491
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