Subcellular Cartography of the Phosphoinositide Multiverse.

Phosphoinositides (PPIn) are low-abundance phospholipids that define membrane identity and direct compartment-specific signaling across eukaryotic cells. Marking fifty years since Michell's seminal 1975 review, we re-evaluate how the subcellular localization of these lipids informs their function. Using a historical and mechanistic framework, we survey evidence for the steady-state distribution of all eight PPIn species and their key precursor, phosphatidic acid, emphasizing live-cell biosensor studies and kinase localization. We conclude that PI(4,5)P₂ and PIP₃ signaling remain largely confined to the plasma membrane, whereas PI4P and PI3P occupy distinct but complementary domains of the Golgi and endosomal systems, and PI(3,5)P₂ marks specialized late endosomal compartments. Together, these patterns reveal PPIn as spatial rather than purely temporal signaling molecules-an ATP-derived currency maintaining the ordered heterogeneity of eukaryotic membranes. Understanding how these pathways self-regulate will define the next generation of phosphoinositide biology.