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Lipids are precisely distributed in cell membranes, along with associated proteins defining organelle identity. Because the major cellular lipid factory is the endoplasmic reticulum (ER), a key issue is to understand how various lipids are subsequently delivered to other compartments by vesicular and non-vesicular transport pathways. Efforts are currently made to decipher how lipid transfer proteins (LTPs) work either across long distances or confined to membrane contact sites (MCSs) where two organelles are at close proximity. Recent findings reveal that proteins of the oxysterol-binding protein related-proteins (ORP)/oxysterol-binding homology (Osh) family are not all just sterol transporters/sensors: some can bind either phosphatidylinositol 4-phosphate (PtdIns(4)P) and sterol or PtdIns(4)P and phosphatidylserine (PS), exchange these lipids between membranes, and thereby use phosphoinositide metabolism to create cellular lipid gradients. Lipid exchange is likely a widespread mechanism also utilized by other LTPs to efficiently trade lipids between organelle membranes. Finally, the discovery of more proteins bearing a lipid-binding module (SMP or START-like domain) raises new questions on how lipids are conveyed in cells and how the activities of different LTPs are coordinated., (© 2016 Authors; published by Portland Press Limited.)

In eukaryotic cells, a sterol gradient exists between the early and late regions of the secretory pathway. This gradient seems to rely on non-vesicular transport mechanisms mediated by specialized carriers. The oxysterol-binding protein-related protein (ORP)/oxysterol-binding homology (Osh) family has been assumed initially to exclusively include proteins acting as sterol sensors/transporters and many efforts have been made to determine their mode of action. Our recent studies have demonstrated that some ORP/Osh proteins are not mere sterol transporters, but sterol/phosphatidylinositol 4-phosphate [PI(4)P] exchangers. They exploit the PI(4)P gradient at the endoplasmic reticulum (ER)/Golgi interface, or at membrane-contact sites between these compartments, to actively create a sterol gradient. Other recent reports have suggested that all ORP/Osh proteins bind PI(4)P and recognize a second lipid that is not necessary sterol. We have thus proposed that ORP/Osh proteins use PI(4)P gradients between organelles to convey various lipid species.

The GTP switch of the small G-protein Arf1 (ADP-ribosylation factor 1) on lipid membranes promotes the polymerization of the COPI (coat protein complex I) coat, which acts as a membrane deforming shell to form transport vesicles. Real-time measurements for coat assembly on liposomes gives insights into how the GTPase cycle of Arf1 is coupled in time with the polymerization of the COPI coat and the resulting membrane deformation. One key parameter seems to be the membrane curvature. Arf-GAP1 (where GAP stands for GTPase-activating protein), which promotes GTP hydrolysis in the Arf1-COPI complex is highly sensitive to lipid packing. Its activity on Arf1-GTP increases by two orders of magnitude as the diameter of the liposomes approaches that of authentic transport vesicles (60 nm). This suggests that during membrane budding, Arf1-GTP molecules are progressively eliminated from the coated area where the membrane curvature is positive, but are protected from Arf-GAP1 at the bud neck due to the negative curvature of this region. As a result, the coat should be stable as long as the bud remains attached and should disassemble as soon as membrane fission occurs.