期刊
JOURNAL OF CELL BIOLOGY
卷 217, 期 5, 页码 1797-1813出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.201710095
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资金
- intramural research program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development at the National Institutes of Health
- National Institutes of Health [1R35GM119412-01]
- Czech Science Foundation [17-05200S]
- Academy of Sciences of the Czech Republic [RVO:61388963]
- Canadian Institutes of Health Research [MOP-133656]
Phosphatidylinositol 4,5-bisphosphate (PI(4,5)P-2) is a critically important regulatory lipid of the plasma membrane (PM); however, little is known about how cells regulate PM PI(4,5)P-2 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)P-2. 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)P-2. Although ORP5 activity requires normal levels of these inositides, ORP8 is called on only when PI(4,5) P-2 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)P-2. Using this rheostat, cells can maintain PI(4,5)P-2 levels by adjusting the availability of PI4P in the PM.
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