Short talk:
Cholesterol promotes head group visibility and clustering of PI(4,5)P2 driving unconventional secretion of Fibroblast Growth Factor 2

Fabio Lolicato1,2, Roberto Saleppico1, Alessandra Griffo3, Bianca Pokrandt1, Hans-Michael Müeller1, Helge Ewers4, Hendrik Hähl3, Jean-Baptiste Fleury3, Ralf Seemann3, Britta Brügger1, Karin Jacobs3, Ilpo Vattulainen2, Walter Nickel1

1Heidelberg University Biochemistry Center BZH, Heidelberg, Germany,
2University of Helsinki, Helsinki, Finland,
3Saarland University, Saarbrücken, Germany,
4Freie Universität Berlin, Berlin, Germany

Fibroblast Growth Factor 2 (FGF2) is a cellular survival factor involved in tumor-induced angiogenesis. It is one of the most prominent examples of extracellular proteins that lack signal peptides and are secreted by ER/Golgi-independent secretory pathways. Biochemical reconstitution experiments and imaging in living cells have shown that FGF2 is secreted by direct translocation across the plasma membrane. This process is initiated by PI(4,5)P2- dependent FGF2 recruitment at the inner plasma membrane leaflet. This in turn results in the formation of membrane-spanning FGF2 oligomers within toroidal membrane pores. Here, using both biochemical reconstitution experiments and live-cell imaging, we demonstrate that PI(4,5)P2-dependent FGF2 recruitment at the inner plasma membrane leaflet is positively modulated by cholesterol in both . Based on extensive molecular dynamics simulations and free energy calculations, we propose cholesterol to increase the negative charge density of the membrane surface and to induce clustering of PI(4,5)P2 molecules stabilizing FGF2 binding through increased avidity. Our findings have general implications for phosphoinositide- dependent protein targeting membranes and explain the highly selective targeting of FGF2 towards the plasma membrane.


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