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Vol. 19, Issue 9, 3871-3884, September 2008

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Coordinated Lipid Transfer between the Endoplasmic Reticulum and the Golgi Complex Requires the VAP Proteins and Is Essential for Golgi-mediated Transport

Diego Peretti^*, Nili Dahan^*, Eyal Shimoni, Koret Hirschberg, and Sima Lev^*

*The Molecular Cell Biology Department and the Electron Microscopy Unit, Weizmann Institute of Science, Rehovot 76100, Israel; and Department of Pathology, Faculty of Medicine, Tel-Aviv University, Ramat Aviv 69978, Israel

Submitted May 19, 2008; Revised June 16, 2008; Accepted June 23, 2008
Monitoring Editor: Vivek Malhotra

Lipid transport between intracellular organelles is mediated by vesicular and nonvesicular transport mechanisms and is critical for maintaining the identities of different cellular membranes. Nonvesicular lipid transport between the endoplasmic reticulum (ER) and the Golgi complex has been proposed to affect the lipid composition of the Golgi membranes. Here, we show that the integral ER–membrane proteins VAP-A and VAP-B affect the structural and functional integrity of the Golgi complex. Depletion of VAPs by RNA interference reduces the levels of phosphatidylinositol-4-phosphate (PI4P), diacylglycerol, and sphingomyelin in the Golgi membranes, and it leads to substantial inhibition of Golgi-mediated transport events. These effects are coordinately mediated by the lipid-transfer/binding proteins Nir2, oxysterol-binding protein (OSBP), and ceramide-transfer protein (CERT), which interact with VAPs via their FFAT motif. The effect of VAPs on PI4P levels is mediated by the phosphatidylinositol/phosphatidylcholine transfer protein Nir2, which is required for Golgi targeting of OSBP and CERT and the subsequent production of diacylglycerol and sphingomyelin. We propose that Nir2, OSBP, and CERT function coordinately at the ER–Golgi membrane contact sites, thereby affecting the lipid composition of the Golgi membranes and consequently their structural and functional identities.

Address correspondence to: Sima Lev (sima.lev{at}weizmann.ac.il)

Abbreviations used: 25OH, 25-hydroxycholesterol; AP1, adaptor complex 1; CERT, ceramide-transport protein; GFP-PKC-C1b, C1b domain of PKC fused to GFP; CCT, CTP:phosphocholine cytidylyltransferase; DAG, diacylglycerol; ER, endoplasmic reticulum; FFAT, two phenylalanines in an acidic tract; KDEL-R, KDEL receptor; LT/BP, lipid-transfer/binding protein; MCS, membrane contact site; ET-18-OCH₃, O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine; OSBP, oxysterol-binding protein; PC, phosphatidylcholine; PH, pleckstrin homology; PI, phosphatidylinositol; PI4K, phosphatidylinositol 4-kinase; PI4P, phosphatidylinositol-4-phosphate; GFP-PKD, protein kinase D; RNAi, RNA interference; siRNA, small interfering RNA; SM, sphingomyelin; TGN, trans-Golgi network; VAP, vesicle-associated membrane protein-associated proteins.

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