PI4P/phosphatidylserine countertransport at ORP5- and ORP8-mediated ER–plasma membrane contacts

Membrane contact sites promote lipid exchange Most membrane lipids are manufactured in the endoplasmic reticulum (ER). Different organelles and the plasma membrane (PM) have distinct phospholipid compositions. Chung et al., working in mammalian cells, and Moser von Filseck et al., working in yeast, both describe how a family of proteins is important in maintaining the balance of lipids within the cell. These special proteins accumulate at and tether contact sites between the ER and the PM and promote the exchange of specific phospholipids, which helps to maintain the PM's distinct identity. Science, this issue pp. 428 and 432 The endoplasmic reticulum proteins ORP5 and ORP8 mediate PI4P-phosphatidylserine exchange at contact sites with the plasma membrane. Lipid transfer between cell membrane bilayers at contacts between the endoplasmic reticulum (ER) and other membranes help to maintain membrane lipid homeostasis. We found that 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.

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