Phosphatidylinositol-4-phosphate

Lipidomics Gateway (25 November 2009) [doi:10.1038/lipidmaps.2009.34]

The precisely regulated metabolism of PI(4)P, the most abundant monophosphorylated inositol phospholipid of mammalian cells, controls essential trafficking processes.

Structure of phosphatidylinositol-4-phosphate. For more molecular information, visit the LIPID MAPS structure database entry

Phosphoinositides (PIs) are derived from phosphatidylinositol. Specific PI kinases and phosphatases control the interconversion of PI species, which can be phosphorylated once, twice, or three times in all combinations of the D-3, D-4 and D-5 positions of the inositol ring. Phosphatidylinositol-4-phosphate, PI(4)P, was historically regarded as an intermediate in the biosynthesis of the prolific signaling lipid PI(4,5)P2. Now, it is recognized as a central controller of important cell functions, particularly in Golgi traffic but increasingly at other subcellular locations too 1 2 .

Maintaining control: It's all about location

PI(4)P functions by recruiting proteins to specific membrane locations. Thus, the distribution of PI(4)P is critical and is tightly controlled by the location and regulation of PI kinases and phosphatases. It is concentrated in Golgi membranes, reflecting its role there, but a recent study suggests that the proportion of PI(4)P at the plasma membrane (PM) has been underestimated due to PM-disruptive staining procedures. Gerald Hammond et al. found that ideal Golgi staining and PM staining conditions for detection of PI(4)P are opposed, and that the majority of PI(4)P turnover occurs at the plasma membrane. This PM pool of PI(4)P is metabolically distinct from the steady-state turnover of PI(4,5)P2 3 .

PI(4)P binding proteins: Complex complexes

The presence of PI(4)P in a membrane would mean nothing without the effector proteins that bind it. Several proteins bind PI(4)P through a pleckstrin homology (PH) or related domain. Some, like the oxysterol binding protein OSBP are involved in lipid transfer, whereas others participate in vesicle formation. These include the coat adaptor protein AP-1 which promotes clathrin-dependent trafficking from the trans-Golgi network 1 . A common feature of PI(4)P binding is the formation of complexes, and specific functions are often regulated by the coincident binding of more than one effector. The regulated presence of these in different locations allows for exquisite fine-tuning of PI(4)P functions. This month in Golgi vesicle formation: Flipping coincidence we highlight the identification of a new effector for PI(4)P in yeast, and a coincidence detection system that regulates Golgi flippase activity and vesicle formation 4 .

Golgi morphology: PI(4)P bridging for budding

Much remains unknown about PI(4)P functions. In October, Seth Field and colleagues reported the identification of GOLPH3 and its yeast homologue Vps74p as PI(4)P binding proteins. With a structure unlike any known PI-binding protein, PI(4)P binding by GOLPH3 emphasizes that many more effectors might be yet unidentified. GOLPH3 also interacts with an unconventional myosin and thus bridges PI(4)P in Golgi membranes to the actin cytoskeleton, generating a tensile force required for vesicle budding, and contributing to the unique Golgi morphology 5 .

Related articles

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Nature Reviews Cancer 9, 530-531 (August 2009) | doi:10.1038/nrc2704

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Emma Leah

References:

  1. Vivinanza, M., D'Angelo, G., Di Campli, A. & De Matteis, M. A. Function and dysfunction of the PI system in membrane trafficking.

    EMBO 27, 2457-2470 (2008). doi:10.1038/emboj.2008.169

  2. D'Angelo, G., Vivinanza, M., Di Campli, A. & De Matteis, M. A. The multiple roles of PtdIns(4)P - not just the precursor of PtdIns(4,5)P2.

    J. Cell Sci. 121, 1955-1963 (2008). doi:10.1242/jcs.023630

  3. Hammond, G. R., Schiavo, G. & Irvine, R. F. Immunocytochemical techniques reveal multiple, distinct cellular pools of PtdIns4P and PtdIns(4,5)P 2.

    Biochem. J. 422, 23-35 (2009). doi:10.1042/BJ20090428

  4. Natarajan, P., Liu, K., Patil, D. V., Sciorra, V.A., Jackson, C. L. & Graham, T.R. Regulation of a Golgi flippase by phosphoinositides and an ArfGEF.

    Nat. Cell Biol. (8 November 2009). doi:10.1038/ncb1989

  5. Dippold, H. C. et al. GOLPH3 Bridges Phosphatidylinositol-4- Phosphate and Actomyosin to Stretch and Shape the Golgi to Promote Budding.

    Cell 139, 337-351 (2009). doi:10.1016/j.cell.2009.07.052

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