Beclin1PI3KC3

Beclin-1 PI3KC3 refers to the Beclin-1–containing class III phosphatidylinositol 3-kinase (PI3K-III) complex, a core regulator of autophagy in mammals. The central core of the complex comprises Beclin-1 (BECN1), VPS34 (PI3KC3) as the catalytic subunit, and VPS15 (p150) as a regulatory partner. In mammals, two major regulatory variants exist: Complex I, which includes ATG14L and primarily drives autophagy initiation at the phagophore; and Complex II, which includes UVRAG and supports autophagosome maturation and endocytic trafficking. Additional factors such as NRBF2 can associate with the complex to modulate activity.

The main enzymatic function of the Beclin-1 PI3KC3 complex is to produce phosphatidylinositol 3-phosphate (PI3P) on membranes. This lipid product serves as a signaling platform that recruits PI3P-binding effector proteins (e.g., WIPI2, DFCP1) to nucleate and expand the autophagic membrane. The assembly and localization of the complex are tightly regulated, ensuring PI3P production occurs at appropriate membranes during autophagy and related trafficking processes.

Regulation of the Beclin-1 PI3KC3 complex involves multiple inputs. Bcl-2 family proteins can bind Beclin-1 and inhibit autophagy, linking autophagy to apoptosis. Upstream signals such as AMPK activation or mTOR suppression enhance complex activity. Post-translational modifications and interactions with partners like Ambra1, UVRAG, and NRBF2 modulate assembly, stability, and subcellular distribution, allowing dynamic control of autophagy in response to cellular conditions.

Dysregulation of the Beclin-1 PI3KC3 complex is implicated in various diseases, including cancer and neurodegenerative disorders, reflecting its central role in autophagy and membrane trafficking. The complex remains a critical focus of research into autophagy regulation and cellular homeostasis.