Mechanisms controlling phosphoinositide synthesis at the plasma membrane

Phosphoinositides (PIPs) are a group of glycerol-based phospholipids that orchestrate many important intracellular signaling pathways via allosteric interactions of their differentially phosphorylated inositol head groups with target proteins. The unique distribution of these lipids within the cytosolic leaflet of intracellular membranes is achieved by the spatiotemporal regulation of the lipid kinases and phosphatases that modify the inositol group. Collectively, the PIPs constitute a lipid-based code of membrane identity critical to cellular function, and dysregulation of PIP homeostasis occurs in many diseases, including cancer, diabetes, neurodegenerative diseases, and viral infections. PI 4-kinases catalyze the conversion of phosphatidylinositol (PI) to PI4P, a biochemical step of fundamental cellular importance, because, at the plasma membrane, PI4P is the precursor to both PI(4,5)P2, a master regulator of signaling, and PI(3,4,5)P3, a major driver of cell growth and oncogenesis. Until recently, little was known about the generation and regulation of this important PI4P pool at the plasma membrane in higher eukaryotes. In my postdoctoral work, I established that the mammalian PI 4-kinase isoform PI4KIIIα, which synthesizes the bulk of the PI4P at the plasma membrane, exists in a protein complex with three non-catalytic adaptor proteins: the palmitoylated membrane anchor EFR3/Rolling blackout, the central scaffold TTC7, and FAM126A/Hyccin, mutations of which cause an inherited brain white matter disease called Hypomyelination and Congenital Cataract (HCC). Functional studies of FAM126A knockout mice and HCC patient tissues suggested that defects in plasma membrane PI4P synthesis  may  underlie  HCC  disease  pathogenesis.  More  broadly,  these  results  have  implicated plasma membrane PI4P synthesis as a pathway promoting myelin formation, a process of essential importance not only in brain development but also during remyelination following injury, as occurs in multiple sclerosis and other demyelinating diseases.