Osbpl9/ORP9 belongs to a large family of oxysterol-binding (OSBP) and OSBP-related proteins (ORP) that has been conserved between yeast and humans.
26,27 Oxysterols regulate cholesterol biosynthesis, uptake, and efflux,
28 but also other biological functions through the liver nuclear receptors (LXRs)
29 that are present in many tissues, including the retina.
30 ORPs have a pleckstrin homology (PH) domain
31 that mediates interaction with phosphatidyl-inositol 4 phosphate (PI-4-P) and is crucial for targeting the proteins to the Golgi complex.
32 They also carry an FFAT consensus sequence that binds VAMP-associated proteins targeting the ORPs to the endoplasmic reticulum.
33 OSBPL9 (or ORP9, as otherwise known) also has a Golgi targeting sequence in its amino terminal end and has been proposed to be a Golgi regulating, cholesterol transfer protein.
34 Although the exact function of each of the ORPs is yet unclear, studies have suggested that they participate in lipid metabolism and act as sensors and transporters of cholesterol and sphingolipids
31,32,35 and that they participate in cell signaling by regulating the activity of the ERK/MAPK pathways.
36 OSBPL9/ORP9 contains a PKC-β phosphorylation site,
37 allowing it to negatively regulate the PDK-2 site at Akt, which is known to control cell survival, cell cycle progression, and glucose metabolism.
37 Thus, upregulation of ORP9 in areas of the retina with extensive damage indicated by RGC loss may result from local signals that involve rapidly diffusible lipids and affect the ER and Golgi apparatus. After all, many of the proteins that are associated with glaucoma in humans appear to have a function in ER/Golgi/endosomal trafficking.
38,39