PIK3R4 (VPS15) serves as the regulatory subunit of class III phosphatidylinositol 3-kinase (PtdIns3K) complexes that are essential for autophagy and endosomal trafficking 1. The protein functions within two distinct complexes: PI3KC3-C1, which initiates autophagosome formation, and PI3KC3-C2, which mediates autophagosome maturation and endocytosis 1. Mechanistically, PIK3R4 contains a pseudokinase domain that regulates the catalytic PIK3C3/VPS34 subunit through conformational changes, with its N-myristate being sequestered in the inactive state and liberated upon membrane-mediated activation 2. The protein forms interactions with various regulatory components, including NRBF2, which specifically binds PIK3R4 to enhance PtdIns3K-C1 activity and promote autophagy 3. PIK3R4 also interacts with FYCO1 to support autophagosome movement and facilitate PI(3)P production required for autophagosome-lysosome fusion 4. Disease relevance includes ciliopathies, where PIK3R4 mutations impair Golgi trafficking and primary cilium formation by affecting IFT20 localization 5. Additionally, PIK3R4 deficiency contributes to immune dysregulation through impaired autophagy, leading to enhanced antigen presentation and aberrant T-cell responses 4. The protein's role extends to maintaining cellular polarity, as demonstrated in Sertoli cells where PIK3C3/PIK3R4 complexes regulate cytoskeletal organization 6.