{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nThe class III phosphatidylinositol 3‐kinase (PIK3C3, also known as Vps34) is a pivotal regulator of autophagy and nutrient‐sensing pathways. Multiple independent studies have shown that in response to amino acids and growth factor cues, PIK3C3 becomes activated to generate phosphatidylinositol‐3‐phosphate (PI3P), a key lipid signal that nucleates autophagosome formation and orchestrates intracellular membrane dynamics. Its activity is tightly controlled by assembly into distinct multiprotein complexes containing Beclin 1, ATG14L, UVRAG, and regulatory subunits such as NRBF2. Moreover, post‐translational modifications – including mTOR‐dependent phosphorylation of complex components, ULK1 activation, acetylation by p300, ubiquitination/deubiquitination cycles, and even lactylation events mediated by glycolytic enzymes – fine‐tune PIK3C3 function to ensure proper autophagic flux, selective cargo degradation (e.g. ribophagy) and termination of the autophagic response when nutrients are replenished."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "27"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its role in autophagy, PIK3C3 is indispensable for proper endocytic trafficking and phagosome maturation. By catalyzing the generation of PI3P on endosomal and phagosomal membranes, it facilitates the recruitment of small GTPases (such as Rab5 and Rab7) and other effectors that are crucial for receptor internalization, maturation of phagosomes, and even the activation of the NADPH oxidase complex during microbial challenge. In some contexts, its association with membrane receptors (for instance, Slamf1) underlies a specialized signaling cascade that links vesicular sorting to innate immune responses and intracellular processing of toxins."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "28", "end_ref": "34"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nPIK3C3’s biological significance extends into disease contexts, including cancer and neurological disorders. Altered expression levels or genetic variations in the PIK3C3 gene have been linked to aberrant autophagy, impaired receptor recycling (such as IL‑7R or EGFR trafficking) and defective cell cycle progression, all of which can contribute to tumor development or progression and even predispose to neuropsychiatric conditions. In several cancer models, disruption of PIK3C3‐dependent autophagy not only exacerbates malignant cell survival and metastasis—for example, via the stabilization or degradation of key epithelial–mesenchymal transition regulators—but also highlights its potential as a therapeutic target. 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