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ORP2 couples LDL‐cholesterol transport to FAK activation by endosomal cholesterol/PI(4,5)P 2 exchange
Author(s) -
Takahashi Kohta,
Kanerva Kristiina,
Vanharanta Lauri,
AlmeidaSouza Leonardo,
Lietha Daniel,
Olkkonen Vesa M,
Ikonen Elina
Publication year - 2021
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.2020106871
Subject(s) - endosome , microbiology and biotechnology , biology , focal adhesion , endocytosis , oxysterol , integrin , cell membrane , cholesterol , cell , biochemistry , signal transduction , intracellular
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.