214: PI(4,5)P2 Asymmetry Accelerates FGF2 Secretion

Kaur M et al., Nature Communications - Reconstitution of asymmetric membranes and matched cell experiments show that transbilayer asymmetry of PI(4,5)P2 lowers the energetic barrier for FGF2-driven lipidic pore formation and enables rapid unconventional secretion. Disrupting PI(4,5)P2 asymmetry in cells blocks FGF2 export. Key terms: FGF2, PI(4,5)P2, membrane asymmetry, unconventional secretion, lipidic pore. Study Highlights:The authors created asymmetric LUVs and GUVs by enzymatic conversion of outer-leaflet PI(4)P to PI(4,5)P2 using PIP5K1C. Time-lapse GUV assays showed that PI(4,5)P2 asymmetry accelerated FGF2-dependent lipidic pore formation (mean ≈45 min asymmetric vs ≈95 min symmetric). In CHO-K1 cells, delivering PI(4,5)P2 to the outer leaflet to disturb asymmetry prevented reappearance of surface FGF2-GFP after heparin wash. Addition of other FGF2-binding phosphoinositides (PI(3,4)P2, PI(3,4,5)P3) similarly inhibited secretion, while PI(4)P and PS did not. Conclusion:Transbilayer asymmetry of PI(4,5)P2 is a key biophysical determinant that facilitates FGF2 oligomer–dependent lipidic pore formation and efficient unconventional secretion. Music:Enjoy the music based on this article at the end of the episode. Article title:Plasma membrane transbilayer asymmetry of PI(4,5)P2 drives unconventional secretion of Fibroblast Growth Factor 2 First author:Kaur M Journal:Nature Communications DOI:10.1038/s41467-025-66860-z Reference:Kaur M, Lolicato F, Nickel W. Plasma membrane transbilayer asymmetry of PI(4,5)P2 drives unconventional secretion of Fibroblast Growth Factor 2. Nat Commun (2025). https://doi.org/10.1038/s41467-025-66860-z License:Creative Commons Attribution 4.0 International (CC BY 4.0) Support:Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 Official website https://basebybase.com On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/episodes/pi45p2-asymmetry-drives-fgf2-secretion QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-11-30. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited the transcript's coverage of PI(4,5)P2 transbilayer asymmetry driving FGF2 secretion, including in vitro asymmetric membranes (LUVs/GUVs), kinase-driven outer-leaflet PI(4,5)P2 generation, cell-based disruption of asymmetry and secretion, lipid controls, kinetics, and recovery dynamics.- transcript topics: FGF2 unconventional secretion overview; PI(4,5)P2 transbilayer asymmetry concept; In vitro reconstitution with asymmetric LUVs/GUVs; PIP5K1C-mediated outer-leaflet PI(4,5)P2 generation and asymmetry verification; Kinetics of FGF2 pore formation in asymmetric vs symmetric membranes; Cell-based disruption of PI(4,5)P2 asymmetry and impact on FGF2 secretion QC Summary:- factual score: 10/10- metadata score: 10/10- supported core claims: 6- claims flagged for review: 0- metadata checks passed: 4- metadata issues found: 0 Metadata Audited:- article_doi- article_title- article_journal- license Factual Items Audited:- Core mechanism: PI(4,5)P2 transbilayer asymmetry lowers energy barrier for FGF2 membrane pore formation.- In vitro, asymmetric PI(4,5)P2 on outer leaflet accelerates pore formation (GUVs) compared with symmetric membranes.- Cell-based disruption of PI(4,5)P2 asymmetry inhibits FGF2 secretion.- Controls show PS and PI(4)P do not inhibit secretion; PI(3,4)P2 and PI(3,4,5)P3 do inhibit secretion.- G... Chapters (00:00:00) - Deep Dive: The physics of cell secretions(00:02:46) - How FGF2 secreates from the cell(00:07:02) - Immunity 7, Asymmetry blocks FGF2 secretion(00:10:24) - What is it about PI4.5p that lowers the energy(00:13:39) - How to Find Your Way Through the Night