Lipid Signaling Regulated by pH: Phosphatidic Acid as a pH Biosensor

Lipids play important roles in signaling in all organisms, yet the underlying regulatory mechanisms are poorly understood. We have taken a systems‐biology approach in yeast to identify new genes and pathways that regulate lipid signaling. We identify over 200 genes that were not previously known to play roles. In the course we uncovered a fundamental mechanism regulating phosphatidic acid (PA) signaling. Binding of a transcription factor, Opi1, to PA depended on cytosolic pH and the protonation state of the lipid's phosphate head‐group. Hence, PA is a lipid pH biosensor and lipid signaling can be regulated directly by pH. We then show that nutrient availability (glucose) regulates phospholipid metabolism to control production of membranes via PA and pH‐dependent lipid signaling. Therefore, we identify a physiological context for pH‐dependent lipid signaling. We propose that lipid pH biosensors play important roles in metabolic regulation in a wide variety of systems.