A Novel Homeostatic Mechanism Tunes PI(4,5)P₂-dependent Signaling at the Plasma Membrane

The lipid molecule phosphatidylinositol (4,5)-bisphosphate (PI(4,5)P₂) controls all aspects of plasma membrane (PM) function in animal cells, from its selective permeability to the attachment of the cytoskeleton. Although disruption of PI(4,5)P₂is associated with a wide range of diseases, it remains unclear how cells sense and maintain PI(4,5)P₂levels to support various cell functions. Here, we show that the PIP4K family of enzymes that synthesize PI(4,5)P₂via a minor pathway, also function as sensors of tonic PI(4,5)P₂levels. PIP4Ks are recruited to the PM by elevated PI(4,5)P₂levels, where they inhibit the major PI(4,5)P₂-synthesizing PIP5Ks. Perturbation of this simple homeostatic mechanism reveals differential sensitivity of PI(4,5)P₂-dependent signaling to elevated PI(4,5)P₂levels. These findings reveal that a subset of PI(4,5)P₂-driven functions may drive disease associated with disrupted PI(4,5)P₂homeostasis.