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.



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.


TC#NameOrganismal TypeExample

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


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

EFF-1B of Caenorhabditis elegans


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)


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


Uncharacterized fusogen protein of 567 aas and 2 TMSs.

Putative fusogen of Trichinella spiralis (Trichina worm)