期刊
EMBO JOURNAL
卷 40, 期 14, 页码 -出版社
WILEY
DOI: 10.15252/embj.2020106871
关键词
cholesterol trafficking; focal adhesion kinase; oxysterol-binding protein-related protein; phosphoinositides; recycling
资金
- Academy of Finland [307415, 324929, 322647]
- Sigrid Juselius Foundation
- Fondation Leducq [19CVD04]
- Jane and Aatos Erkko Foundation
- Magnus Ehrnrooth Foundation
- Finnish Foundation for Cardiovascular Research
- Helsinki Institute of Life Science (HiLIFE)
- Ministry of Science, Innovation and Universities [RTI2018-099318-B-I00]
- Academy of Finland (AKA) [324929, 324929, 322647] Funding Source: Academy of Finland (AKA)
The study reveals the mechanism by which ORP2 regulates lipid and protein trafficking in cells, controlling FAK activation and LDL-cholesterol plasma membrane delivery by facilitating cholesterol and PI(4,5)P-2 exchange between late and recycling endosomes.
Low-density lipoprotein (LDL)-cholesterol delivery from late endosomes to the plasma membrane regulates focal adhesion dynamics and cell migration, but the mechanisms controlling it are poorly characterized. Here, we employed auxin-inducible rapid degradation of oxysterol-binding protein-related protein 2 (ORP2/OSBPL2) to show that endogenous ORP2 mediates the transfer of LDL-derived cholesterol from late endosomes to focal adhesion kinase (FAK)-/integrin-positive recycling endosomes in human cells. In vitro, cholesterol enhances membrane association of FAK to PI(4,5)P-2-containing lipid bilayers. In cells, ORP2 stimulates FAK activation and PI(4,5)P-2 generation in endomembranes, enhancing cell adhesion. Moreover, ORP2 increases PI(4,5)P-2 in NPC1-containing late endosomes in a FAK-dependent manner, controlling their tubulovesicular trafficking. Together, these results provide evidence that ORP2 controls FAK activation and LDL-cholesterol plasma membrane delivery by promoting bidirectional cholesterol/PI(4,5)P-2 exchange between late and recycling endosomes.
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