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Description
Fibroblast Growth Factor 2 (FGF2) is a key cell survival factor involved in tumor-induced angiogenesis. Unlike most secreted proteins, FGF2 lacks a signal peptide and is exported via unconventional protein secretion (UPS), bypassing the ER/Golgi. It translocates directly across the plasma membrane (Type I UPS), a process initiated by PI(4,5)P₂- mediated recruitment to the inner leaflet. Subsequently, FGF2 forms membrane-spanning oligomers within toroidal membrane pores. The final stage of secretion involves heparan sulfate proteoglycans on the cell surface, which disassemble these oligomers at the outer membrane leaflet, ensuring FGF2 is released into the extracellular space to mediate autocrine and paracrine signaling. Using atomic force microscopy, biochemical reconstitution experiments, and multiscale molecular physics-based computer simulations, we show that FGF2 self-assembles into a ring-like structure, triggering PI(4,5)P₂ lipid sorting and membrane remodeling. When PI(4,5)P₂ reaches a critical threshold, its non-bilayer properties destabilize the membrane, forming a pore through which FGF2 translocate across the membrane. We propose that the geometry of FGF2 oligomers and their lipid sorting capacity are crucial for protein translocation, suggesting a shared mechanism with other pore-forming proteins that assemble into ring-like structures