PI4K

Phosphatidylinositol 4-kinases (PI4Ks) are a family of lipid kinases that catalyze the phosphorylation of phosphatidylinositol (PI) at the 4-position to generate phosphatidylinositol 4-phosphate (PI4P). PI4P is a central membrane lipid that helps organize membrane trafficking and signaling by defining specific membrane identities, particularly at the Golgi apparatus, endosomes, and the plasma membrane. PI4Ks are found in eukaryotic cells and are essential for proper vesicle formation, cargo sorting, and lipid homeostasis.

In humans, PI4Ks are grouped into two main classes: type II and type III. The type II family includes PI4K2A and PI4K2B, which are smaller enzymes associated with endosomal and lysosomal membranes. The type III family comprises PI4KA and PI4KB, larger catalytic proteins that generate PI4P at the Golgi and other membranes and form membrane-associated complexes with regulatory subunits. The four human genes encoding these enzymes are PI4KA, PI4KB, PI4K2A, and PI4K2B.

PI4KA, the alpha isoform, normally functions with regulatory partners such as TTC7-FAM126 and EFR3 to establish PI4P pools at the ER-Golgi interface and the plasma membrane. PI4KB, the beta isoform, contributes to Golgi PI4P production and is exploited by certain RNA viruses to form replication organelles. Type II PI4Ks contribute to PI4P generation at endomembrane compartments in a context-specific manner.

Physiological roles of PI4Ks include providing docking sites for PI4P-binding effector proteins and serving as precursors for other phosphoinositides. Disruption of PI4K activity impairs secretion, trafficking, and organelle identity. Mutations or dysregulation of PI4KA have been linked to neurodevelopmental disorders, and PI4Ks are active research targets for antiviral strategies. Small molecules that selectively inhibit PI4Ks have been developed to probe function and explore therapeutic potential.