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)P2 is associated with a wide range of diseases, it remains unclear how cells sense and maintain PI(4,5)P2 levels to support various cell functions. Here, we show that the PIP4K family of enzymes that synthesize PI(4,5)P2 via a minor pathway, also function as sensors of tonic PI(4,5)P2 levels, inactivating synthesis of the lipid via the major PIP5K-catalyzed pathway when PI(4,5)P2 levels rise. Perturbation of this simple homeostatic mechanism reveals differential sensitivity of PI(4,5)P2-dependent signaling to elevated PI(4,5)P2 levels. These finding reveal that a subset of PI(4,5)P2-driven functions may drive disease associated with disrupted PI(4,5)P2 homeostasis. One-Sentence Summary The enzyme PIP4K functions as both a sensor and negative regulator of PI(4,5)P2 synthesis by the closely related PIP5K enzymes, tuning the activity of numerous membrane functions. ### Competing Interest Statement The authors have declared no competing interest.