How cells fuse

Abstract

Cell-cell fusion remains the least understood type of membrane fusion process. However, the last few years have brought about major advances in understanding fusion between gametes, myoblasts, macrophages, trophoblasts, epithelial, cancer, and other cells in normal development and in diseases. While different cell fusion processes appear to proceed via similar membrane rearrangements, proteins that have been identified as necessary and sufficient for cell fusion (fusogens) use diverse mechanisms. Some fusions are controlled by a single fusogen; other fusions depend on several proteins that either work together throughout the fusion pathway or drive distinct stages. Furthermore, some fusions require fusogens to be present on both fusing membranes, and in other fusions, fusogens have to be on only one of the membranes. Remarkably, some of the proteins that fuse cells also sculpt single cells, repair neurons, promote scission of endocytic vesicles, and seal phagosomes. In this review, we discuss the properties and diversity of the known proteins mediating cell-cell fusion and highlight their different working mechanisms in various contexts.

Figure 1.

Mechanisms of cell–cell fusion. (A) The pathway of cell–cell fusion. Ready-to-fuse cells (1) recognize and closely appose each other (2) and undergo hemifusion (3), i.e., the merger of the outer monolayers of two membrane bilayers, allowing redistribution of the lipid markers between the cells (note that both distal monolayers of the membranes and cell contents remain distinct). Opening of a fusion pore in the hemifusion structure allows the mixing of the cytoplasmic contents (4), and pore expansion completes joining of two cells into one (5). While Myomaker/Myomerger, syncytins, and fusexins seem to be for now the only proteins necessary for specific fusion processes, they are most likely working with other players, some of which, especially for myoblasts, are already identified. Fusexins and syncytins mediate all the stages of the fusion process; in contrast, Myomaker is required for an early stage involving the transition to hemifusion, while Myomerger is required for a later stage between hemifusion and opening of fusion pores (see the main text). (B) Schematic representation of the lipid rearrangements during the events explained in A. LPC blocks hemifusion by inhibiting the bending of the contacting monolayers (Chernomordik and Kozlov, 2003). (C) Inset from A 2: Protein fusogens are necessary to overcome the energetic barriers of hemifusion and opening and expansion of the fusion pore. Examples display bilateral and homotypic fusions mediated by C. elegans EFF-1 (upper panel) and Arabidopsis HAP2 (middle panel) as well as a bilateral and heterotypic fusion between them (lower panel; Valansi et al., 2017).

Figure 2.

Alternative functions for cell–cell fusogens. Membrane remodeling activity of EFF-1 and AFF-1 proteins is not limited to mediating cell–cell fusion events. Auto-fusion: a single cell fuses with itself to form donut-shaped cells that can stack and elongate to form tubes, or alternatively join a severed process, as in neuronal regeneration. Extracellular vesicle fusion: AFF-1 proteins can mediate the fusion between a vesicular carrier and the cell. Phagocytosis (EFF-1–mediated) and endocytosis (AFF-1–mediated): Fission events occur to seal the fission pore of the forming intracellular vesicle. Note that while endoplasmic fusogens (e.g., SNAREs and atlastins) act from the cytoplasmic space (light blue areas), EFF-1 and AFF-1 cell–cell fusogens induce fusion from the extracellular space (exoplasmic fusogens in white areas).