PI3KC3

PI3KC3 / VPS34 is the single Class III PI3K that produces PI3P, supporting endosome-lysosome trafficking and autophagy induction^[1]. Mechanistically, PI3KC3 complex I contains VPS34, VPS15, BECN1, and ATG14, and initiates macroautophagy through PI3P synthesis at autophagosome formation sites^[2]. In autophagy models, VPS34 kinase-domain dynamics regulate PI3KC3-C1 activity and autophagy induction^[3]. In disease-relevant systems, PI3KC3 supports vesicular trafficking, endocytosis, and autophagosome-autolysosome formation in podocytes, while endosomal-autophagic-lysosomal dysregulation appears in Alzheimer’s disease mouse brain regions^[4][5]. Compared with Class I PI3K isoforms that synthesize PIP3, Class III PI3K synthesizes PI3P and regulates endosome-lysosome trafficking and autophagy^[1]. For experimental applications, SAR405 selectively inhibits PIK3C3/VPS34, disrupts late endosome-to-lysosome trafficking, blocks starvation- or MTOR-inhibition-induced autophagy, and synergizes with everolimus in renal tumor cells^[6].