Research Plasma membrane transbilayer asymmetry of PI(4,5)P2 drives unconventional secretion of Fibroblast Growth Factor 2

The Nickel and Lolicato groups have uncovered how the asymmetric plasma membrane transbilayer distribution of the membrane lipid PI(4,5)P₂ drives unconventional secretion of Fibroblast Growth Factor 2 (FGF2). Using complimentary in vitro reconstitution systems and cell-based assays, the team demonstrated that PI(4,5)P₂ transbilayer asymmetry strongly promotes FGF2 membrane translocation. The study shows that this asymmetry is essential for efficient secretion: while enhancing asymmetry boosts FGF2 membrane translocation in vitro, disrupting asymmetry inhibits FGF2 secretion from cells. These findings provide direct mechanistic evidence that PI(4,5)P₂ asymmetry lowers the energetic barrier for membrane pore formation, enabling rapid membrane translocation, the underlying mechanism of unconventional secretion of FGF2.