Lipid traffic: an enigmatic alliance between ORPs and a TMEM16-like protein at membrane contact sites

Lipid transfer proteins (LTPs) play a critical role in distributing lipids within eukaryotic cells. In yeast, Osh6 and Osh7, which belong to the oxysterol-binding protein-related protein family, transfer phosphatidylserine (PS) from the endoplasmic reticulum (ER) to the plasma membrane (PM) in exchange for phosphatidylinositol 4-phosphate (PI(4)P). These proteins localize at ER-PM contact sites by associating with Ist2, an ER-resident TMEM16-like protein that bridges the ER and PM via a long intrinsically disordered region (IDR). Recent studies have shown that this association ensures accurate PS transfer by concentrating Osh6 and Osh7 at the ER-PM interface while preserving their ability to access both membranes. However, it remains unclear how these LTPs function when bound to the Ist2 IDR, whose length far exceeds the ER-PM distance at contact sites, and why they do not integrate both the tethering and the PS/PI(4)P exchange functions, like their human homologs. Additionally, it has been revealed that Ist2 can transfer lipids across the ER membrane via a scramblase activity. Yet, whether and why this activity is coupled to the PS/PI(4)P exchange activity of Osh6 and Osh7 remains unknown. The Ist2-Osh6/7 system emerges as a fascinating model that integrates tethering, scramblase, and lipid exchange functions. Future studies of this system are likely to provide important insights into how lipid transfer processes are coordinated at membrane contact sites.