️ Episode 214: PI(4,5)P2 Asymmetry Enables Rapid FGF2 Secretion

In this episode of PaperCast Base by Base, we explore This study shows that an asymmetric transbilayer distribution of PI(4,5)P2 lowers the energy barrier for lipidic pore formation and accelerates unconventional secretion of Fibroblast Growth Factor 2

Study Highlights:
The authors generated asymmetric LUVs and GUVs by enzymatically converting outer-leaflet PI(4)P to PI(4,5)P2 using PIP5K1C and validated PI(4,5)P2 presence with FGF2-GFP and FGF2-Halo binding assays. GUV reconstitution assays revealed that outer-leaflet enrichment of PI(4,5)P2 shortened mean FGF2-dependent pore formation times from ~95 minutes to ~45 minutes without changing final pore frequency. In CHO-K1 cells, delivery of exogenous PI(4,5)P2 to the outer leaflet disrupted transbilayer asymmetry and acutely inhibited FGF2 secretion, an effect mirrored by PI(3,4)P2 and PI(3,4,5)P3 but not by PI(4)P or phosphatidylserine. Exogenously added PI(4,5)P2 was cleared from the cell surface within 40–60 minutes and FGF2 secretion recovered, supporting a reversible, asymmetry-dependent mechanism

Conclusion:
Transbilayer asymmetry of PI(4,5)P2 is a key biophysical determinant that lowers the energetic cost of membrane pore opening and is required for fast unconventional secretion of FGF2

Music:
Enjoy the music based on this article at the end of the episode.

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:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

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On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics.

Episode link: https://basebybase.castos.com/episodes/pi45p2-transbilayer-asymmetry

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