Phosphatidylinositol 4,5-bisphosphate (PIP2) is an anionic signaling lipid. Its polyunsaturated acyl chains exclude it from GM1 lipid rafts.[5][6] The multiple negative charges on PIP2 are thought to cluster proteins with positive charges residing in the plasma membrane leading to nanoscale clusters. PIP3 is also clustered away from PIP2 and away from GM1 lipid rafts.
PIP2 domains inhibit GM1 domain function by attracting palmitoylated proteins away from GM1 lipid rafts.[7] For this to occur, a protein must be bothpalmitoylated and bind PIP2. Presumably PIP2 could also antagonize PIP3 localization but this has not been shown directly.
Phospholipase D2 (PLD2) binds PIP2 and localizes with lipid rafts. Increases in cholesterol overcome PIP2 binding and sequester PLD2 into GM1 lipid rafts away from its substratephosphatidylcholine. Efflux of cholesterol causes PLD2 to translocate to PIP2 domains where it is activated bysubstrate presentation.[8] Both PIP2 signaling andcholesterol signaling regulate the enzyme.
Angiotensin converting enzyme (ACE2) is regulated by PIP2 localization. The ACE2 enzyme is palmitoylated which drives the protein into GM1 lipids. The enzyme also bind to PIP2 which moves it out of the endocytic pathway. The drughydroxychloroquine blocks ACE2 interaction with PIP2 in multiple cell types shifting its localization.[9]
