VPS34IN1IN2

VPS34IN1IN2 is a protein encoded by the VPS34IN1IN2 gene in Homo sapiens. It functions as a dual inhibitor of the class III phosphatidylinositol 3‑kinase VPS34, the central catalytic subunit of the PI3K‑III complex that generates phosphatidylinositol 3‑phosphate (PI3P). By binding to VPS34 and the regulator Beclin‑1, VPS34IN1IN2 reduces PI3P production, thereby modulating autophagosome formation, endolysosomal trafficking, and vesicular transport.

The protein is composed of two distinct inhibitor domains, referred to as VPS34IN1 and VPS34IN2, which correspond to complementary regions of the protein that interact with different sites on the VPS34 complex. Loss‑of‑function mutations in VPS34IN1IN2 lead to increased autophagic flux and heightened degradation of cellular debris, whereas overexpression of VPS34IN1IN2 suppresses autophagy and can result in accumulation of protein aggregates.

Expression of VPS34IN1IN2 is highest in neurons, liver, and skeletal muscle, suggesting a key role in the maintenance of neuronal homeostasis and metabolic regulation. In mouse models, deletion of the VPS34IN1IN2 locus accelerates neurodegeneration under stress conditions, while its overexpression protects against diet‑induced hepatic steatosis.

VPS34IN1IN2 has been implicated in several disease contexts. Genome‑wide association studies have linked polymorphisms in VPS34IN1IN2 to increased risk of Parkinson’s disease, likely due to impaired autophagic clearance of damaged mitochondria. In addition, altered VPS34IN1IN2 expression has been reported in certain cancers, where it appears to influence cell proliferation and response to chemotherapy.

The protein is further regulated by post‑translational modifications such as phosphorylation and ubiquitination, which fine‑tune its interaction with the VPS34 complex. Ongoing research seeks to clarify the structural basis for VPS34 inhibition and to explore therapeutic targeting of VPS34IN1IN2 in neurodegenerative disease and cancer.