9.A.68 The FF Fusogen (FFF) Family
The FFF (Also called EFF-AFF) family of proteins mediates myoblast fusion (Smurova and Podbilewicz 2016). FFFs are essential to fuse cells in the skin, reproductive, excretory, digestive and nervous systems in nematodes. EFF-1 (Epithelial Fusion Failure 1), a member of the FFF family, is a type I membrane glycoprotein that is essential for most cell fusions in C. elegans. The crystal structure of EFF-1 ectodomain reveals striking structural similarity to class II fusion glycoproteins from enveloped viruses (e.g. dengue and rubella) that mediate virus to cell fusions. Smurova and Podbilewicz 2016 found EFF-1 to be present on the plasma membrane and in RAB-5-positive early endosomes, with EFF-1 recycling between these 2 cell compartments. Only when EFF-1 proteins transiently arrive to the surfaces of 2 adjacent cells do they dynamically interact in trans and mediate membrane fusion.
EFF-1 is continuously internalized by receptor-mediated endocytosis via the activity of 2 small GTPases: RAB-5 and Dynamin. Smurova and Podbilewicz 2016 proposed a model that explains how EFF-1 endocytosis together with interactions in trans can control cell-cell fusion. Kontani et al. 2005 showed that vacuolar ATPase (vATPase) mutations result in EFF-1-dependent hyperfusion (Kontani and Rothman 2005). Smurova and Podbilewicz 2016 proposed that vATPase is required for normal degradation of EFF-1. Failure to degrade EFF-1 results in delayed hyperfusion and mislocalization to organelles that appear to be recycling endosomes. EFF-1 is also required to fuse neurons as part of the repair mechanism following injury and to prune dendrites. Possibly EFF-1 regulates neuronal tree-like structures via endocytosis. Thus, endocytosis of cell-cell fusion proteins mzy function to prevent merging of cells and to sculpt organs and neurons.