phosphatidylinositol3phosphate

Phosphatidylinositol 3-phosphate (PI3P) is a phosphatidylinositol lipid phosphorylated at the 3-position of the inositol head group. It is a minor but essential phosphoinositide enriched on early endosomal membranes and autophagosomes in many eukaryotes.

Biosynthesis and localization: PI3P is produced primarily by the Class III PI3-kinase complex containing VPS34, Beclin-1, Vps15, and regulatory subunits. In mammalian cells, different VPS34 complexes (complex I for autophagy, complex II for endosomal trafficking) generate PI3P on distinct membrane compartments, coordinating membrane dynamics.

Function: PI3P serves as a docking lipid that recruits effector proteins bearing PI3P-binding motifs, notably FYVE and PX domains (examples include EEA1 and HRS). Through these interactions, PI3P promotes early endosome fusion, cargo sorting, and endosomal maturation, as well as initiation of autophagy by recruiting autophagy-related factors to forming phagophores.

Metabolism and turnover: PI3P is removed by 3-phosphatases such as the myotubularin family, generating phosphatidylinositol. The balance of production and dephosphorylation controls PI3P levels on membranes and thereby influences trafficking and autophagic activity.

Detection and relevance: PI3P-enriched membranes can be visualized in the lab using PI3P-binding probes based on FYVE or PX domains fused to fluorescent proteins. Abnormal PI3P signaling has been linked to various diseases, including neurodegenerative disorders and cancer. Pharmacological inhibition of VPS34, which reduces PI3P production, is under investigation as a potential therapeutic approach.