VPS34

VPS34 is the catalytic subunit of the class III phosphatidylinositol 3-kinase (PI3K) complex and is encoded by the PIK3C3 gene in humans. It functions as a lipid kinase that phosphorylates phosphatidylinositol to generate phosphatidylinositol 3-phosphate (PI(3)P), a lipid signal that helps recruit downstream effector proteins to membranes.

In eukaryotes, VPS34 operates within two main conserved complexes. Complex I, which includes VPS34, the regulatory subunit VPS15 (p150), Beclin-1, and ATG14L, drives autophagy initiation and the formation of autophagosomes. Complex II comprises VPS34, VPS15, Beclin-1, and UVRAG, and is more closely tied to endocytic trafficking and endosome maturation. Regulators such as NRBF2 and AMBRA1 can modulate complex assembly and activity, while Beclin-1–Bcl-2 interactions provide a link to cellular stress and survival pathways.

PI(3)P produced by VPS34 serves as a platform for the recruitment of PX and FYVE domain-containing proteins involved in membrane trafficking, endosome maturation, and autophagosome nucleation. The activity of VPS34 is subject to regulation by nutrient and stress signals, and it is inhibited by some pharmacological inhibitors used in research.

Dysregulation of VPS34 activity has been associated with various diseases, including cancer and neurodegenerative disorders, reflecting its central role in autophagy and endocytic pathways. Due to its essential cellular functions, VPS34 is a focus of research into mechanisms of autophagy and membrane trafficking, as well as potential therapeutic targeting.