Inter‐organelle sterol transfer activity of oxysterol binding proteins

Oxysterol‐binding protein (OSBP) and OSBP‐related proteins (ORPs) comprise a 12‐member gene family implicated in cholesterol metabolism, signaling and transport. OSBP/ORPs are characterized by a C‐terminal sterol‐binding domain, as well as pleckstrin homology (PH) and FFAT domains that mediate ′dual localization′ to organelles. OSBP and ORP9 localize specifically to the endoplasmic reticulum (ER) and trans‐Golgi network (TGN) by virtue of PH and FFAT domains. Both proteins have cholesterol extraction and transfer activity in vitro , suggesting that a primary activity is sterol transfer between these organelles. In this context, OSBP regulates Golgi and post‐Golgi cholesterol content and phosphatidylinositol 4‐kinase IIα activity, resulting in recruitment of the ceramide transfer protein CERT and increased sphingomyelin (SM) synthesis. In contrast, ORP9 does not affect SM synthesis, but regulates post‐Golgi cholesterol content, and Golgi structure and secretion. We propose that sterol transfer by OSBP and ORP9 regulate cholesterol‐dependent activities in distinct ER‐Golgi compartments. By extension, the varied biological functions of other family members could be the result of a primary transport activity that regulates sterol‐dependent activities in target membranes.