Endocrine Abstracts

Phosphoinositides (PIs) serve crucial roles in cell physiology ranging from cell signalling to membrane traffic. Among the seven eukaryotic PIs the best studied species is phosphatidylinositol (4,5)-bisphosphate (PI(4,5)P₂), which is concentrated at the plasma membrane where among many other functions it is required for the nucleation of endocytic clathrin-coated pits (CCPs). No PI other than PI(4,5)P₂ has been implicated in clathrin-mediated endocytosis (CME), whereas the subsequent endosomal stages of the endocytic pathway are dominated by PI 3-phosphates. How PI conversion from PI(4,5)P₂-positive endocytic intermediates to PI 3-phosphate (PI(3)P)-containing endosomes and, conversely, from PI(3)P-positive endosomes to plasma membrane PI(4,5)P₂ is achieved is unclear.

In my talk I will summarize our recent findings regarding the mechanisms of PI conversion between the plasma membrane and endosomes. We recently demonstrated that formation of phosphatidylinositol-3, 4-bisphosphate (PI(3,4)P₂) by class II phosphatidylinositol 3-kinase C2α (PI3K C2α) spatiotemporally controls CME by regulating maturation of late-stage CCPs before fission. Timed formation of PI(3,4)P₂ by PI3K C2α is required for selective enrichment of the BAR domain protein SNX9 at late-stage endocytic intermediates. Combined mathematical modelling, super-resolution imaging, and genetic manipulations provide a mechanistic framework for PI conversion from PI(4,5)P₂ to PI(3,4)P₂ en route to endosomes. Furthermore, I will discuss our most recent data on the role of PI conversion in endosomal homeostasis and recycling to the plasma membrane.