Flagging fusion: Phosphatidylserine signaling in cell-cell fusion

Abstract

Formations of myofibers, osteoclasts, syncytiotrophoblasts, and fertilized zygotes share a common step, cell-cell fusion. Recent years have brought about considerable progress in identifying some of the proteins involved in these and other cell-fusion processes. However, even for the best-characterized cell fusions, we still do not know the mechanisms that regulate the timing of cell-fusion events. Are they fully controlled by the expression of fusogenic proteins or do they also depend on some triggering signal that activates these proteins? The latter scenario would be analogous to the mechanisms that control the timing of exocytosis initiated by Ca²⁺ influx and virus-cell fusion initiated by low pH- or receptor interaction. Diverse cell fusions are accompanied by the nonapoptotic exposure of phosphatidylserine at the surface of fusing cells. Here we review data on the dependence of membrane remodeling in cell fusion on phosphatidylserine and phosphatidylserine-recognizing proteins and discuss the hypothesis that cell surface phosphatidylserine serves as a conserved "fuse me" signal regulating the time and place of cell-fusion processes.

Keywords: membrane fusion; myogenesis; osteoclast; phosphatidylserine; placenta.

Figure 1

Phosphatidylserine (PS) exposure and fusion through hemifusion unite disparate fusion processes. Cell–cell fusion processes, including fusion of osteoclast precursors, myoblast fusion, sperm–egg fusion, and trophoblast, are preceded by dissimilar differentiation processes (1) and produce cells (osteoclasts, myotubes, zygote, syncytiotrophoblast) strikingly different in their properties and functions (4). In spite of this diversity, the actual membrane fusion event in all these processes apparently proceeds through a conserved pathway of membrane rearrangements, in which PS exposure on the cell surface (2) is followed by formation of early hemifusion intermediates and the opening of fusion pores (3).

Figure 2

Some mechanisms of phosphatidylserine (PS) exposure at the plasma membrane in nonapoptotic cells. Cartoon depicting potential mechanisms of PS exposure in biological processes. At rest, PS (shown as lipids with red polar heads) is asymmetrically oriented toward the cytosolic face of the plasma membrane (top), however in some biological contexts PS is transiently exposed on the extracellular facing leaflet by the activation of professional phospholipid scramblases (left, middle), the formation of lipidic or partially lipidic pores (center, middle), or fusion between PM and intracellular vesicles carrying PS in their inner (lumen-exposed) leaflet (right, middle).

Figure 3

Proposed mechanisms of cell-fusion regulation by PS exposure. We suggest that exofacial PS either directly promotes fusogenic restructuring of protein fusogen (illustrated by the pathway at the top) or triggers assembly of the fusion machinery (pathway at the bottom). Starting from the left, two fusion-committed cells prepare membrane fusion. In the first scenario, binding of protein fusogens (blue) to PS (red) exposed at the surface of the cells triggers restructuring of the fusion, depicted here by the hypothetical closing of a “hinge-like” fusogen. In the second scenario, PS interactions with PS-binding proteins (yellow) trigger assembly and activation of the fusion machinery. Finally, the conformational energy discharged in either mechanism promotes the union of fusion partner membranes and the opening of a fusion pore between them (right).