VPS15

VPS15, also known as vacuolar protein sorting 15 homolog, is a regulatory subunit of the class III phosphatidylinositol 3-kinase (PI3K) complex. In humans, the VPS15 protein is encoded by the PIK3R4 gene and is the yeast Vps15 homolog. The class III PI3K complex catalyzes the phosphorylation of phosphatidylinositol to produce phosphatidylinositol 3-phosphate (PI(3)P), a lipid signal essential for endosome sorting and autophagy.

VPS15 forms a core complex with the catalytic subunit VPS34 (PIK3C3) and accessory components such as Beclin 1 (BECN1) and ATG14L in the autophagy-initiating complex. It also participates in a separate complex that can include UVRAG, contributing to broader endosomal trafficking processes. VPS15 stabilizes the VPS34 catalytic subunit, regulates its kinase activity, and helps recruit the complex to membranes, thereby controlling PI(3)P production on endosomal and autophagosomal membranes.

Functionally, the VPS15-containing complex is involved in endocytic trafficking, endosome maturation, and autophagy. In autophagy, the complex promotes initiation by recruiting Beclin 1 and ATG14L, leading to autophagosome formation. The regulatory subunit is generally considered catalytically inactive but essential for proper complex assembly and localization.

Mutations or altered expression of VPS15 have been investigated in contexts such as cancer and neurodegenerative diseases, where autophagy and endosomal trafficking pathways are disrupted. The protein's broad expression pattern aligns with a housekeeping role in membrane trafficking processes and cellular homeostasis.

See also: PI3K class III, PIK3C3, Beclin 1, ATG14L, UVRAG.