Cholesterol transport in the late endocytic pathway: Roles of ORP family proteins

Oxysterol-binding protein (OSBP) homologues, designated ORP or OSBPL proteins, constitute one of the largest families of intracellular lipid-binding/transfer proteins (LTP). This review summarizes the mounting evidence that several members of this family participate in the machinery facilitating cholesterol trafficking in the late endocytic pathway. There are indications that OSBP, besides acting as a cholesterol/phosphatidylinositol 4-phosphate (PI4P) exchanger at the endoplasmic reticulum (ER)-trans-Golgi network (TGN) membrane contact sites (MCS), also exchanges these lipids at ER-lysosome (Lys) contacts, increasing Lys cholesterol content. The long isoform of ORP1 (ORP1L), which also targets ER-late endosome (LE)/Lys MCS, has the capacity to mediate cholesterol transport either from ER to LE or in the opposite direction. Moreover, it regulates the motility, positioning and fusion of LE as well as autophagic flux. ORP2, the closest relative of ORP1, is mainly cytosolic, but also targets PI(4,5)P₂-rich endosomal compartments. Our latest data suggest that ORP2 transfers cholesterol from LE to recycling endosomes (RE) in exchange for PI(4,5)P₂, thus stimulating the recruitment of focal adhesion kinase (FAK) on the RE and cell adhesion. FAK activates phosphoinositide kinase on the RE to enhance PI(4,5)P₂ synthesis. ORP2 in turn transfers PI(4,5)P₂ from RE to LE, thus regulating LE tubule formation and transport activity.