AUTHOR=Lolicato Fabio , Nickel Walter 

TITLE=A Role for Liquid-Ordered Plasma Membrane Nanodomains Coordinating the Unconventional Secretory Pathway of Fibroblast Growth Factor 2?

JOURNAL=Frontiers in Cell and Developmental Biology

VOLUME=Volume 10 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2022.864257

DOI=10.3389/fcell.2022.864257

ISSN=2296-634X

ABSTRACT=Fibroblast Growth Factor 2 (FGF2) is a tumor cell survival factor that belongs to a sub-group of extracellular proteins lacking N-terminal signal peptides.  While this phenomenon has already been recognized in the early 1990ies, detailed insights into the molecular mechanisms underlying alternative pathways of protein secretion from eukaryotic cells were obtained only recently.  Today, we know about a number of alternative secretory mechanisms, collectively termed unconventional protein secretion (UPS).  FGF2 belongs to a sub-group of cargo proteins secreted by direct translocation across the plasma membrane.  This feature has been classified as type I UPS and is shared with other unconventionally secreted proteins such as HIV-Tat, Tau and, under certain physiological conditions, Interleukin 1β.  FGF2 translocation across the membrane is initiated through sequential interactions with the Na,K-ATPase, Tec kinase, and the phosphoinositide PI(4,5)P2 at the inner plasma membrane leaflet.  While the first two are auxiliary factors of this pathway, the interaction of FGF2 with PI(4,5)P2 triggers the core mechanism of FGF2 membrane translocation.  It is based on PI(4,5)P2-induced oligomerization of FGF2 concomitant with the formation of a lipidic membrane pore.  Membrane-inserted FGF2 oligomers have been recognized as translocation intermediates that are resolved at the outer plasma membrane leaflet by glypican-1, a heparan sulfate proteoglycan that captures and disassembles FGF2 oligomers on cell surfaces.  Here, we discuss recent findings suggesting the molecular machinery mediating FGF2 membrane translocation to be highly organized in liquid-ordered plasma membrane nanodomains, the core process underlying this unusual pathway of protein secretion.