PI4KIII

Phosphatidylinositol 4-kinase type III (PI4KIII) refers to a family of class III phosphatidylinositol kinases that catalyze the ATP-dependent phosphorylation of phosphatidylinositol (PI) to produce phosphatidylinositol 4-phosphate (PI4P). PI4P serves as a key lipid signaling molecule and membrane trafficking platform, helping define membrane identity and recruit effector proteins.

In humans, the two principal paralogs are PI4KIIIα and PI4KIIIβ, encoded by the PI4KA and PI4KB genes, respectively. Although they share a catalytic core, their regulation and localization differ. PI4KIIIα forms a membrane-associated complex with TTC7 and FAM126A, which stabilizes the enzyme and promotes PI4P production at the plasma membrane and related compartments. PI4KIIIβ is recruited to Golgi membranes by ACBD3 and generates PI4P crucial for Golgi function and post-Golgi trafficking. These distinct PI4P pools help control different steps of membrane trafficking and lipid homeostasis.

Function and significance: The PI4P produced by PI4KIII enzymes acts as a docking site for a variety of effector proteins containing PI4P-binding domains, coordinating vesicle formation, cargo sorting, and lipid transfer. PI4P also participates in autophagy and helps maintain organelle identity at the Golgi and plasma membrane.

Regulation and research relevance: PI4KIII activity is regulated by protein-protein interactions and cellular localization. Select inhibitors, such as PIK93, have been used to study PI4KIII-dependent processes. The enzymes play a role in viral replication for several viruses, including hepatitis C virus, which relies on PI4KIIIβ to form replication organelles, highlighting potential antiviral targets.

Overall, PI4KIII enzymes are essential for normal membrane trafficking and lipid signaling in eukaryotic cells.