PI(4,5)P2 controls plasma membrane PI4P and PS levels via ORP5/8 recruitment to ER–PM contact sites

• Published in: The Journal of cell biology Vol. 217; no. 5; pp. 1797 - 1813
• Main Authors: Sohn, Mira, Korzeniowski, Marek, Zewe, James P., Wills, Rachel C., Hammond, Gerald R.V., Humpolickova, Jana, Vrzal, Lukas, Chalupska, Dominika, Veverka, Vaclav, Fairn, Gregory D., Boura, Evzen, Balla, Tamas
• Format: Journal Article
• Language: English
• Published: Rockefeller University Press 07.05.2018
• ISSN: 0021-9525; 1540-8140
• DOI: 10.1083/jcb.201710095

Phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) is a critically important regulatory lipid of the plasma membrane (PM); however, little is known about how cells regulate PM PI(4,5)P2 levels. Here, we show that the phosphatidylinositol 4-phosphate (PI4P)/phosphatidylserine (PS) transfer activity of the endoplasmic reticulum (ER)–resident ORP5 and ORP8 is regulated by both PM PI4P and PI(4,5)P2. Dynamic control of ORP5/8 recruitment to the PM occurs through interactions with the N-terminal Pleckstrin homology domains and adjacent basic residues of ORP5/8 with both PI4P and PI(4,5)P2. Although ORP5 activity requires normal levels of these inositides, ORP8 is called on only when PI(4,5)P2 levels are increased. Regulation of the ORP5/8 attachment to the PM by both phosphoinositides provides a powerful means to determine the relative flux of PI4P toward the ER for PS transport and Sac1-mediated dephosphorylation and PIP 5-kinase–mediated conversion to PI(4,5)P2. Using this rheostat, cells can maintain PI(4,5)P2 levels by adjusting the availability of PI4P in the PM.