pH Biosensing by PI4P Regulates Cargo Sorting at the TGN

Phosphoinositides, diacylglycerolpyrophosphate, ceramide-1-phosphate, and phosphatidic acid belong to a unique class of membrane signaling lipids that contain phosphomonoesters in their headgroups having pKa values in the physiological range. The phosphomonoester headgroup of phosphatidic acid enables this lipid to act as a pH biosensor as changes in its protonation state with intracellular pH regulate binding to effector proteins. Here, we demonstrate that binding of pleckstrin homology (PH) domains to phosphatidylinositol 4-phosphate (PI4P) in the yeast trans-Golgi network (TGN) is dependent on intracellular pH, indicating PI4P is a pH biosensor. pH biosensing by TGN PI4P in response to nutrient availability governs protein sorting at the TGN, likely by regulating sterol transfer to the TGN by Osh1, a member of the conserved oxysterol-binding protein (OSBP) family of lipid transfer proteins. Thus, pH biosensing by TGN PI4P allows for direct metabolic regulation of protein trafficking and cell growth. [Display omitted] •PI4P in the TGN senses changes in intracellular pH via protonation of its headgroup•pH via protonation of PI4P regulates recruitment of effector proteins to the TGN•pH-dependent recruitment of Osh1 to TGN PI4P regulates cargo sorting at the TGN•Glucose regulates pH and Osh1 TGN localization coupling nutrients to trafficking PI4P is an important signaling lipid in the TGN regulating adapter recruitment and cargo trafficking. Shin et al. show that a change in intracellular pH in response to glucose governs the protonation state of TGN PI4P, which controls recruitment of Osh1 and cargo sorting at the TGN.