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Vol. 20, Issue 5, 1388-1399, March 1, 2009

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Oxysterol Binding Protein–related Protein 9 (ORP9) Is a Cholesterol Transfer Protein That Regulates Golgi Structure and Function

Departments of Pediatrics, and Biochemistry and Molecular Biology, Atlantic Research Centre, Dalhousie University, Halifax, Nova Scotia, Canada B3H 4H7

Submitted September 3, 2008; Revised December 3, 2008; Accepted December 24, 2008
Monitoring Editor: Howard Riezman

Oxysterol-binding protein (OSBP) and OSBP-related proteins (ORPs) constitute a large gene family that differentially localize to organellar membranes, reflecting a functional role in sterol signaling and/or transport. OSBP partitions between the endoplasmic reticulum (ER) and Golgi apparatus where it imparts sterol-dependent regulation of ceramide transport and sphingomyelin synthesis. ORP9L also is localized to the ER–Golgi, but its role in secretion and lipid transport is unknown. Here we demonstrate that ORP9L partitioning between the trans-Golgi/trans-Golgi network (TGN), and the ER is mediated by a phosphatidylinositol 4-phosphate (PI-4P)-specific PH domain and VAMP-associated protein (VAP), respectively. In vitro, both OSBP and ORP9L mediated PI-4P–dependent cholesterol transport between liposomes, suggesting their primary in vivo function is sterol transfer between the Golgi and ER. Depletion of ORP9L by RNAi caused Golgi fragmentation, inhibition of vesicular somatitus virus glycoprotein transport from the ER and accumulation of cholesterol in endosomes/lysosomes. Complete cessation of protein transport and cell growth inhibition was achieved by inducible overexpression of ORP9S, a dominant negative variant lacking the PH domain. We conclude that ORP9 maintains the integrity of the early secretory pathway by mediating transport of sterols between the ER and trans-Golgi/TGN.

Address correspondence to: Neale D. Ridgway (nridgway{at}dal.ca)

Abbreviations used: CERT, ceramide transfer protein; ER, endoplasmic reticulum; FFAT, two phenylalanines in an acidic tract; GlcCer, glucosylceramide; LPDS, lipoprotein-deficient serum; OSBP, oxysterol-binding protein; ORP, OSBP-related protein; PC, phosphatidylcholine; PE, phosphatidylethanolamine; PH, pleckstrin homology; PI-3P, phosphatidylinositol 3-phosphate; PI-4P, phosphatidylinositol 4-phosphate; PI-5P, phosphatidylinositol 5-phosphate; TGN, trans-Golgi network; VAP, vesicle-associated membrane protein–associated protein; VSVG, vesicular stomatitus virus glycoprotein.

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