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

Elsa Meneses-Salas, Ana García-Melero, Kristiina Kanerva, Patricia Blanco-Muñoz, Frederic Morales-Paytuvi, Júlia Bonjoch, Josefina Casas, Antonia Egert, Syed S. Beevi, Jaimy Jose, Vicenta Llorente-Cortés, Kerry-Anne Rye, Joerg Heeren, Albert Lu, Albert Pol, Francesc Tebar, Elina Ikonen, Thomas Grewal, Carlos Enrich, Carles Rentero

Research output: Contribution to journalArticlepeer-review

28 Citations (Scopus)
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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.
Original languageEnglish
Pages (from-to)2839-2857
Number of pages19
JournalExperientia
Volume77
Issue number14
Early online date29 Oct 2019
DOIs
Publication statusPublished - 2020

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