1.N.4 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 (Pérez-Vargas et al. 2014). 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. Reviewed by Hernández and Podbilewicz 2017. 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 and Rothman 2005 and 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.
References:
Hernández, J.M. and B. Podbilewicz. (2017). The hallmarks of cell-cell fusion. Development 144: 4481-4495.
Hindi, S.M., M.M. Tajrishi, and A. Kumar. (2013). Signaling mechanisms in mammalian myoblast fusion. Sci Signal 6: re2.
Kontani, K. and J.H. Rothman. (2005). Cell fusion: EFF is enough. Curr. Biol. 15: R252-254.
Kontani, K., I.P. Moskowitz, and J.H. Rothman. (2005). Repression of cell-cell fusion by components of the C. elegans vacuolar ATPase complex. Dev Cell 8: 787-794.
Pérez-Vargas, J., T. Krey, C. Valansi, O. Avinoam, A. Haouz, M. Jamin, H. Raveh-Barak, B. Podbilewicz, and F.A. Rey. (2014). Structural basis of eukaryotic cell-cell fusion. Cell 157: 407-419.
Procko, C., Y. Lu, and S. Shaham. (2011). Glia delimit shape changes of sensory neuron receptive endings in C. elegans. Development 138: 1371-1381.
Sapir, A., J. Choi, E. Leikina, O. Avinoam, C. Valansi, L.V. Chernomordik, A.P. Newman, and B. Podbilewicz. (2007). AFF-1, a FOS-1-regulated fusogen, mediates fusion of the anchor cell in C. elegans. Dev Cell 12: 683-698.
Shinn-Thomas, J.H., J.J. del Campo, J. Wang, and W.A. Mohler. (2016). The EFF-1A Cytoplasmic Domain Influences Hypodermal Cell Fusions in C. elegans But Is Not Dependent on 14-3-3 Proteins. PLoS One 11: e0146874.
Smurova, K. and B. Podbilewicz. (2016). Endocytosis regulates membrane localization and function of the fusogen EFF-1. Small GTPases 1-4. [Epub: Ahead of Print]
Soulavie, F. and M.V. Sundaram. (2016). Auto-fusion and the shaping of neurons and tubes. Semin Cell Dev Biol 60: 136-145.
Examples:
TC#	Name	Organismal Type	Example
1.N.4.1.1	EFF-1A of 658 aas and 2 TMSs, N- and C-terminal. Required for normal cell fusion. The EFF-1A endodomain is required for normal rates of EFF-1-dependent epidermal cell fusions (Shinn-Thomas et al. 2016).		EFF1A of Caenorhabditis elegans

1.N.4.1.2	EFF-1B of 596 aas and 2 TMSs, N- and C-terminal (Kontani and Rothman 2005).		EFF-1B of Caenorhabditis elegans

1.N.4.1.3	Myoblast syncytium formation protein generated by plasma membrane fusion of 852 aas and 4 - 5 TMSs. The roles of the major signaling pathways in mammalian myoblast fusion have been reviewed (Hindi et al. 2013).		FFF protein of Branchiostoma floridae (Florida lancelet) (Amphioxus)

1.N.4.1.4	Cell fusion protein, AFF-1 of 589 aas and 2 TMSs, one N-terminial and one C-terminal (Soulavie and Sundaram 2016). Required for cell fusion events during development including the fusion of anchor cells (AC), vulval A and vulval D rings, and late epidermal seam cells (Sapir et al. 2007). In response to environmental stressors, C. elegans enters a diapause state, termed dauer, which is accompanied by remodeling of sensory neuron receptive endings, dependent on AFF-1 (Procko et al. 2011).		AFF-1 of Caenorhabditis elegans

1.N.4.1.5	Uncharacterized fusogen protein of 567 aas and 2 TMSs.		*Putative fusogen of Trichinella spiralis* (Trichina worm)**