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

Autor: Meneses-Salas E., García-Melero A., Kanerva K., Blanco-Muñoz P., Morales-Paytuvi F., Bonjoch J., Casas J., Egert A., Beevi S.S., Jose J., Llorente-Cortés V., Rye K.-A., Heeren J., Lu A., Pol A., Tebar F., Ikonen E., Grewal T., Enrich C., Rentero C.
Rok vydání: 2020
Předmět:
calphobindin II
CHO cell line
fat droplet
animal cell
Endoplasmic Reticulum
StARD3 gene
STARD3 protein
human
Rab protein
membrane protein
animal
genetics
cell interaction
Annexin A6
cellular distribution
cholesterol acyltransferase
GTPase-Activating Proteins
TBC1D15 protein
human
protein domain
Niemann-Pick Disease
Type C
Niemann-Pick disease cell line
Cholesterol
gene inactivation
TBC1D15 gene
protein transport
lipid storage
Rab7 gene
Niemann Pick disease
CHO Cells
Endosomes
Article
animal tissue
Cricetulus
Animals
Humans
controlled study
human
gene
endosome
mouse
guanosine triphosphatase activating protein
nonhuman
electron microscopy
protein depletion
Cell Membrane
Membrane Proteins
enzyme activation
small interfering RNA
carrier protein
gene function
pathology
AnxA6 gene
Rab7 protein
Carrier Proteins
Protein D
metabolism
Zdroj: CELLULAR AND MOLECULAR LIFE SCIENCES
r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
instname
ISSN: 1420-682X
Popis: 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).
Databáze: OpenAIRE
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