Our bodies and our cells need specialized fats. Our cells eat through a process called endocytosis, which is critical for cells to take up nutrients from their environment. Embedded in the cell membrane, phosphoinositides are specialized lipids crucial during endocytosis and subsequent steps. They can be modified by protein kinases and phosphatases that alter their phosphorylation pattern in one of five places, indicated by the number(s) in the name. Thus was born the PIP family. PIP2, for example, is PtdIns(4,5)P2 phosphorylated in positions 4 and 5.
Although their structures are very similar, each PIP has a unique role in the cell. Dysfunction in the kinases and phosphatases that generate the phosphoinositides can lead to diseases such as cancer and Lowe syndrome, a rare sex-linked genetic disorder that can affect the eyes, brain, and kidneys. Phosphatidylinositol-4,5-bisphosphate [PtdIns(4,5)P2] is known to be critical for endocytosis to proceed. No other phosphoinositide has been implicated in this process. Now comes evidence for a new PIP2.
The new study led by York Posor, a graduate student at the Freie Universität Berlin, recently published in Nature1, introduces a different PIP2 into the endocytic process: PtdIns(3,4)P2. The result surprised endocytosis researchers, who thought of PtdIns(4,5)P2 as the only PIP2 in endocytosis. Evidently, the role of phosphoinositides is more complex than previously anticipated.
The researchers show that the new PIP2 (PtdIns(3,4)P2) localized to endocytic sites and that a kinase (PI3K C2α) comes to these sites to phosphorylate the old PIP2, after it is dephosphorylated to become PtdIns(4)P, thus generating the new PIP2 version, PtdIns(3,4)P2. Then, using live-cell TIRF microscopy, the researchers showed that the kinase appears before and during the recruitment of scission protein, dynamin. They also indentified an interaction between PtdIns(3,4)P2 and sorting nexin 9, a protein involved in the late stages of endocytosis.
The subtle change in the position of PIP2 phosphorylation led to recruitment of an important endocytic protein, sorting nexin 9. All of this is of great interest to cell biologists but a reminder to a world of eaters that even a pathway as well studied as endocytosis can still have unexpected twists. When our cells sit down to eat, unexpected guests can still reveal themselves at table.