Cells adapt to extracellular acidic pH through TM9SF3-mediated PI(4,5)P2 flop

Abstract

The plasma membrane (PM), a physical barrier separating cells from their environment, responds to fluctuating extracellular environment through receptor-mediated signaling. While these pathways have been extensively studied, the role of PM lipids remains poorly understood. Here, we show that phosphatidylinositol 4,5-bisphosphate (PIP₂), a multifunctional phospholipid, translocates from the inner to the outer leaflet of the PM in response to extracellular acidification. A genome-wide screening identifies Transmembrane 9 superfamily 3 (TM9SF3) as a critical regulator for PIP₂ translocation. During zebrafish gastrulation, when intracellular pH increases and extracellular interstitial fluid pH decreases, mutant anterior axial mesoderm lacking Tm9sf3 exhibits disorganized collective cell migration due to impaired PIP₂-dependent cytoskeletal organization. Our results demonstrate that TM9SF3 mediates the PIP₂ translocation when cells encounter a low pH for adapting the cells to their environment. Given that "pH-dependent PIP₂ translocation" is evolutionarily conserved, cells may broadly employ lipid topology as a strategy to respond to extracellular stimuli.