Abstract The lipid molecule phosphatidylinositol (4,5)-bisphosphate (PI(4,5)P 2 ) 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)P 2 is associated with a wide range of diseases, it remains unclear how cells sense and maintain PI(4,5)P 2 levels to support various cell functions. Here, we show that the PIP4K family of enzymes that synthesize PI(4,5)P 2 via a minor pathway, also function as sensors of tonic PI(4,5)P 2 levels. PIP4Ks are recruited to the PM by elevated PI(4,5)P 2 levels, where they inhibit the major PI(4,5)P 2 -synthesizing PIP5Ks. Perturbation of this simple homeostatic mechanism reveals differential sensitivity of PI(4,5)P 2 -dependent signaling to elevated PI(4,5)P 2 levels. These findings reveal that a subset of PI(4,5)P 2 -driven functions may drive disease associated with disrupted PI(4,5)P 2 homeostasis. One-Sentence Summary The enzyme PIP4K functions as both a sensor and negative regulator of PI(4,5)P 2 synthesis by the closely related PIP5K enzymes, tuning the activity of numerous membrane functions.

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