Beclin1VPS34VPS15ATG14L

Beclin-1–Vps34–Vps15 complex, also known as the class III phosphatidylinositol 3-kinase (PI3K-III) complex, is a central regulator of autophagy and endocytic trafficking. The core complex consists of Beclin-1 (BECN1), the lipid kinase Vps34 (PIK3C3), and the regulatory subunit Vps15 (PIK3R4). In mammalian cells, accessory factors determine its specific role: Atg14L/Barkor associates to form Complex I that initiates autophagy by directing PI3P production to the nascent autophagosomal membrane; UVRAG associates in Complex II, promoting endocytic maturation and membrane trafficking independent of autophagy. The kinase activity of Vps34 generates phosphatidylinositol 3-phosphate (PI3P), which recruits PI3P-binding effector proteins to sites of vesicle nucleation and autophagosome formation.

Beclin-1 is negatively regulated by Bcl-2 family proteins, which bind to Beclin-1 and prevent complex formation. Disruption of this interaction by cellular stress or phosphorylation events relieves inhibition and promotes autophagy. Nutrient status, through mTOR signaling, and various post-translational modifications fine-tune complex assembly and activity.

Dysregulation or mutation of components of the PI3K-III complex has been linked to diseases such as cancer, neurodegenerative disorders, and infections, reflecting its essential role in autophagy and membrane trafficking.