Science 337, 727–730 (2012)

Phosphatidylinositol 4-phosphate (PI4P) residing in the membrane of the Golgi apparatus has several ascribed functions, whereas the PI4P found in the plasma membrane (PM) was thought to serve only as a substrate for the kinase PIP5K to generate PI(4,5)P2, which has numerous roles at the PM, including regulation of cell signaling and membrane traffic. To test for a potential PM role of PI4P, Hammond et al. enzymatically depleted the PM of either PI4P or PI(4,5)P2. They found that the majority of PM PI4P is not required to maintain steady-state concentrations of PI(4,5)P2 and is dispensable for maintaining the functionally relevant pool of PI(4,5)P2, which must be continuously resynthesized. Instead, the authors found that PI4P contributes to the pool of polyanionic lipids that contribute to the inner PM leaflet's negative charge. In fact, both PI4P and PI(4,5)P2 are required for binding of nonspecific electrostatic PM-binding proteins. Finally, PI4P contributes to and can substitute for PI(4,5)P2 in regulation of TRPV1 channel activation, yet it had no effect on TRPM8 channels, which are specifically dependent on PI(4,5)P2. These results suggest that PI4P fulfills some of the roles of PI(4,5)P2 so that the latter lipid is available to regulate its large repertoire of effectors while the electrostatic properties of the PM are maintained.