Unconventional Secretion of Fibroblast Growth Factor 2—A Novel Type of Protein Translocation across Membranes?

N-terminal signal peptides are a hallmark of the vast majority of soluble secretory proteins that are transported along the endoplasmic reticulum/Golgi-dependent pathway. They are recognized by signal recognition particle, a process that initiates membrane translocation into the lumen of the endoplasmic reticulum followed by vesicular transport to the cell surface and release into the extracellular space. Beyond this well-established mechanism of protein secretion from eukaryotic cells, a number of extracellular proteins with critical physiological functions in immune surveillance and tissue organization are known to be secreted in a manner independent of signal recognition particle. Such processes have collectively been termed “unconventional protein secretion” and, while known for more than two decades, their underlying mechanisms are only beginning to emerge. Different types of unconventional secretory mechanisms have been described with the best-characterized example being based on direct translocation of cytoplasmic proteins across plasma membranes. The aim of this review is to critically assess our current knowledge of this type of unconventional secretion focusing on fibroblast growth factor 2 (FGF2) as the most established example. [Display omitted] •Unconventional secretion of FGF2 is based on a novel mechanism of protein translocation across plasma membranes.•This pathway is initiated by phosphoinositide-dependent recruitment at the inner leaflet.•Phosphoinositide-dependent recruitment causes FGF2 to oligomerize concomitant with the formation of a lipidic membrane pore.•Pore formation as a translocation intermediate is facilitated by Tec-kinase-mediated phosphorylation of FGF2.•Cell surface heparan sulfates are required to complete FGF2 translocation by extracellular trapping.