Mini-reviewRunning up that hill: How to create cellular lipid gradients by lipid counter-flows

- Sterol/PI4P exchangers can create de novo a sterol gradient between two membranes.
- OSBP mediates sterol/PI4P counter-flows in ER-Golgi contact sites.
- A subset of ORP/Osh proteins acts as PS/PI4P exchangers at ER/PM interface.
- Viruses accelerate OSBP's exchange activity to build replication organelles in cells.
- ORPhilin drugs block sterol/PI4P exchanges to exert an antiviral activity.

Lipids are unevenly distributed within eukaryotic cells, allowing various processes to work in an optimized membrane environment. Rather than following vesicular trafficking pathways, certain lipids are transported by lipid transfer proteins (LTPs), some at sites of close apposition of two organelles called membrane contact sites (MCSs). An important question is whether or not LTPs are able to convey lipids to create and maintain the lipid gradients observed between organelles. Recent data shows that LTPs from the ORP/Osh family transport sterols and phosphatidylserine (PS) to the Golgi and plasma membrane, respectively, through counter-exchange for the phosphoinositide phosphatidylinositol 4-phosphate (PI4P). Coupling PI4P-driven exchange to PI4P metabolism allows for an accumulation of these lipids in specific organelles and for a regulation of ORP/Osh proteins in MCSs. Additionally, data indicate that PI4P/sterol exchanges are hijacked by various virus strains to generate replication organelles. Compounds called ORPhilins block PI4P/sterol exchange and have thereby powerful antiviral activities, indicating in turn that some ORP/Osh proteins might be relevant pharmaceutical targets.