2.D.1 The PI4P/PS Counter Transporter (P/P-CT) Family 

Lipid transfer between cell membrane bilayers at contacts between the endoplasmic reticulum (ER) and other membranes help to maintain membrane lipid homeostasis. Two similar ER integral membrane proteins, oxysterol-binding protein (OSBP)-related protein 5 (ORP5) and ORP8, tethered the ER to the plasma membrane (PM) via the interaction of their pleckstrin homology domains with phosphatidylinositol 4-phosphate (PI4P) in this membrane. Their OSBP-related domains (ORDs) harbored either PI4P or phosphatidylserine (PS) and exchanged these lipids between bilayers. Gain- and loss-of-function experiments showed that ORP5 and ORP8 could mediate PI4P/PS countertransport between the ER and the PM, thus delivering PI4P to the ER-localized PI4P phosphatase Sac1 for degradation and PS from the ER to the PM. This exchange helps to control plasma membrane PI4P levels and selectively enrich PS in the PM (Chung et al. 2015).

In eukaryotic cells, PS is synthesized in the ER but is highly enriched in the PM where it contributes negative charge and specific recruitment of signaling proteins. This distribution relies on transport mechanisms involving the yeast PS transporter Osh6p extracting phosphatidylinositol 4-phosphate (PI4P) and exchanging PS for PI4P between the two membranes. The crystal structure of Osh6p:PI4P complex has been solved (Moser von Filseck et al. 2015).and the transport of PS by Osh6p depends on PI4P recognition in vivo. The PI4P-phosphatase Sac1p, maintains a PI4P gradient at the ER/PM interface, to drive PS transport. Thus, PS transport by oxysterol-binding protein-related protein (ORP)/oxysterol-binding homology (Osh) proteins is fueled by PI4P metabolism through PS/PI4P exchange cycles.