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).