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.

Department of Cell Biology University of Pittsburgh School of Medicine Pittsburgh PA

Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences Prague Czech Republic

Keenan Research Centre for Biomedical Science St Michael's Hospital Toronto ON Canada

Section on Molecular Signal Transduction Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health Bethesda MD

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Crystal Structure of the ORP8 Lipid Transport ORD Domain: Model of Lipid Transport

Defining the subcellular distribution and metabolic channeling of phosphatidylinositol

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PDB
1V88

RefSeq
NM_020896, NM_008844

GENBANK
BC111728, AF048695