2026-04-17T06:10:38Zhttps://recercat.cat/oai/request

oai:recercat.cat:2445/1486712025-11-20T14:44:38Zcom_2072_1057col_2072_478780col_2072_478858col_2072_478917

00925njm 22002777a 4500 dc Meneses Salas, Elsa author García Melero, Ana author Kanerva, Kristiina author Blanco Muñoz, Patricia author Morales Paytuvi, Frederic author Bonjoch, Júlia author Casas Brugulat, Josefina author Egert, Antonia author Beevi, Syed S. author Jose, Jaimy author Llorente Cortés, Vicenta author Rye, Kerry-Anne author Heeren, Joerg author Lu, Albert author Pol i Sorolla, Albert author Tebar Ramon, Francesc author Ikonen, Elina author Grewal, Thomas author Enrich Bastús, Carles author Rentero Alfonso, Carles author 2020-01-24T18:33:53Z 2020-01-24T18:33:53Z 2019-10-29 2020-01-24T18:33:53Z 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. Colesterol Proteïnes de membrana Cholesterol Membrane proteins Annexin A6 modulates TBC1D15/Rab7/StARD3 axis to control endosomal cholesterol export in NPC1 cells