1.G.9 The Syncytin (Syncytin) Family Syncytin-1 of the endogenous defective retrovirus HERV-W, is a 'captive' retroviral envelope protein involved in placental morphogenesis (Mi et al., 2000). The viral protein has assumed an important function in mammalian physiology. Expression of recombinant syncytin induces formation of giant syncytia, and fusion of a human trophoblast cell line is mediated by syncytin. Thus, syncytin, a probable viral membrane fusion protein, mediates placental cytotrophoblast fusion in vivo, and thus is important for human placental morphogenesis (Mi et al., 2000). The ERVW-1 receptor is SLC1A5/ASCT-2/RDR/ATB₀, a sodium-dependent neutral amino acid transporter B₀ (2.A.23.3.3), and their interaction is mediated by connexin 43. Both proteins are essential for trophoblast cell fusion (Dunk et al., 2012). Fusion in the placenta is facilitated by syncytin 1 and syncytin 2. These syncytins arose from retroviral sequences that entered the primate genome 25 million and more than 40 million years ago, respectively. Syncytins and their receptors are involved in fusion events during human reproduction and during tumorigenesis. (Soygur and Sati 2016). The effects of individually silenced N-glycosylation sites and non-synonymous single-nucleotide polymorphisms on the fusogenic function of human syncytin-2 have been demonstrated (Cui et al. 2016).Syncytins have bee reviewed by Hernández and Podbilewicz 2017.
This family belongs to the Viral Envelope Fusion Protein (Env-FP) Superfamily.
References:
Apellaniz B., Huarte N., Largo E. and Nieva JL. (2014). The three lives of viral fusion peptides. Chem Phys Lipids. 181:40-55.
Blond, J.L., D. Lavillette, V. Cheynet, O. Bouton, G. Oriol, S. Chapel-Fernandes, B. Mandrand, F. Mallet, and F.L. Cosset. (2000). An envelope glycoprotein of the human endogenous retrovirus HERV-W is expressed in the human placenta and fuses cells expressing the type D mammalian retrovirus receptor. J. Virol. 74: 3321-3329.
Blond, J.L., F. Besème, L. Duret, O. Bouton, F. Bedin, H. Perron, B. Mandrand, and F. Mallet. (1999). Molecular characterization and placental expression of HERV-W, a new human endogenous retrovirus family. J. Virol. 73: 1175-1185.
Bui, S., J. Dancourt, and G. Lavieu. (2023). Virus-Free Method to Control and Enhance Extracellular Vesicle Cargo Loading and Delivery. ACS Appl Bio Mater 6: 1081-1091.
Cui, L., H. Wang, X. Lu, R. Wang, R. Zheng, Y. Li, X. Yang, W.T. Jia, Y. Zhao, Y. Wang, H. Wang, Y.L. Wang, C. Zhu, H.Y. Lin, and H. Wang. (2016). Effects of individually silenced N-glycosylation sites and non-synonymous single-nucleotide polymorphisms on the fusogenic function of human syncytin-2. Cell Adh Migr 10: 39-55.
Dunk, C.E., A. Gellhaus, S. Drewlo, D. Baczyk, A.J. Pötgens, E. Winterhager, J.C. Kingdom, and S.J. Lye. (2012). The molecular role of connexin 43 in human trophoblast cell fusion. Biol Reprod 86: 115.
Hernández, J.M. and B. Podbilewicz. (2017). The hallmarks of cell-cell fusion. Development 144: 4481-4495.
Lavillette, D., M. Marin, A. Ruggieri, F. Mallet, F.L. Cosset, and D. Kabat. (2002). The envelope glycoprotein of human endogenous retrovirus type W uses a divergent family of amino acid transporters/cell surface receptors. J. Virol. 76: 6442-6452.
Mi, S., X. Lee, X. Li, G.M. Veldman, H. Finnerty, L. Racie, E. LaVallie, X.Y. Tang, P. Edouard, S. Howes, J.C. Keith, Jr, and J.M. McCoy. (2000). Syncytin is a captive retroviral envelope protein involved in human placental morphogenesis. Nature 403: 785-789.
Mousseau, G., N. Préault, S. Souquere, C. Bireau, P. Cassonnet, A. Bacquin, L. Beck, G. Pierron, Y. Jacob, A. Dupressoir, and T. Heidmann. (2024). Sodium-dependent phosphate transporter PiT1/SLC20A1 as the receptor for the endogenous retroviral envelope syncytin-B involved in mouse placenta formation. J. Virol. 98: e0091524.
Soygur, B. and L. Sati. (2016). The role of syncytins in human reproduction and reproductive organ cancers. Reproduction 152: R167-178.
Štafl, K., M. Trávníček, A. Janovská, D. Kučerová, &.#.3.1.7.;. Pecnová, Z. Yang, V. Stepanec, L. Jech, M.S. Salker, J. Hejnar, and K. Trejbalová. (2024). Receptor usage of Syncytin-1: ASCT2, but not ASCT1, is a functional receptor and effector of cell fusion in the human placenta. Proc. Natl. Acad. Sci. USA 121: e2407519121.
Štafl, K., M. Trávníček, D. Kučerová, &.#.3.1.7.;. Pecnová, V. Krchlíková, E. Gáliková, V. Stepanets, J. Hejnar, and K. Trejbalová. (2021). Heterologous avian system for quantitative analysis of Syncytin-1 interaction with ASCT2 receptor. Retrovirology 18: 15.
Sugimoto, J., M. Sugimoto, H. Bernstein, Y. Jinno, and D. Schust. (2013). A novel human endogenous retroviral protein inhibits cell-cell fusion. Sci Rep 3: 1462.
Examples:
TC#	Name	Organismal Type	Example
1.G.9.1.1	HERV-W_7q21.2 provirus ancestral Env polyprotein (ENV-W; gPr73; enverin; syncytin-1, HERV-7q envelope protein) (Blond et al., 1999; Mi et al., 2000). This endogenous retroviral envelope protein, encoded within the human genome, has retained its original fusogenic properties and participates in trophoblast fusion and the formation of a syncytium during placenta morphogenesis. It may induce fusion through binding of SLC1A4 and SLC1A5 (Blond et al. 2000; Lavillette et al. 2002; Sugimoto et al. 2013. Syncytin-1 interacts with the ASCT2 receptor (Štafl et al. 2021). It also participates in virus-free extracellular vesicle cargo loading and delivery (see TC# 8.A. 40.1.19) (Bui et al. 2023).	Animal virus	*HERV-W_7q21.2 of Homo sapiens* (Q9UQF0)**

1.G.9.1.2	Syncytin 2 of 538 aas. Syncytins maintain cell-cell fusogenic activity based on ENV: gene-mediated viral cell entry but promote fusion of various cells during development in humans (Soygur and Sati 2016). Receptor usage of Syncytin-1: ASCT2, but not ASCT1, is a functional receptor and effector of cell fusion in the human placenta (Štafl et al. 2024).		Syncytin 2 of Homo sapiens

1.G.9.1.3	Syncytin-B of 618 aas with several TMSs, possibly as many as 6, with one N-terminal, one C-terminal, and 4 internal at residues 120, 170, 360 and 440. PiT1/SLC20A1 is the receptor for the endogenous retroviral envelope syncytin-B involved in mouse placenta formation (Mousseau et al. 2024).		Syncytin-B of Mus musculus

Examples:
TC#	Name	Organismal Type	Example
1.G.9.2.1	Envelope glycoprotein, Env, of 654 aas and 3 TMSs, one N-terminal, one C-terminal and one at about residue 473.	Virus	Env of porcine endogenous retrovirus A

1.G.9.2.2	The human T-lymphotropic virus type 1 (HTLV-1) glycoprotein gp21 of 121 aas and containing the N-terminal 25 aa fusion peptide with a single TMS.	Retroviridae	gp21 of the human T-lymphotropic virus type 1 (HTLV-1)

1.G.9.2.3	The Human T-cell leukemia virus 1, HTLV-1, of 488 aas and 2 or 3 TMSs, N- and C-terminal with a possible additional TMS at residue 320. The glycine-rich region of this transmembrane protein is involved in membrane fusion. It is a class I viral fusion protein (Wilson et al. 2005). The N-terminal fusion peptide initiates virus-cell membrane fusion. The fusion peptide is linked to the coiled-coil core through a conserved sequence that is rich in glycines. Wilson et al. 2005 investigated the functional role of the glycine-rich segment, Met-326 to Ser-337, of gp21. Alanine substitution for the hydrophobic residue Ile-334 caused a 90% reduction in cell-cell fusion activity without a detectable effect on the lipid-mixing and pore forming phases of fusion. Retroviral glycoprotein fusion thus appears to require flexibility within the glycine-rich segment and hydrophobic contacts mediated by this segment (Wilson et al. 2005).		HTLV-1 of T-cell leukemia virus 1

1.G.9.2.4	Envelope glycoprotein of 259 aas with 12 N-terminal TMS, Env.	Virus	Env of Human T-cell leukemia virus 2 (HTLV-2)

1.G.9.2.5	Envelope glycoprotein of 214 aas (partial), Gp30, with 2 TMSs, one at the N-terminus, and one at residues 140 - 160.	Viruses	Gp30 of bovine leukemia viru

1.G.9.2.6	Envolope glycoprotein of 341 aas and 3 TMSs, one N-terminal and two C-terminal, gPr72. Three YXXL sequences of a Bovine Leukemia Virus TEnv transmembrane protein are independently required for fusion activity by controlling expression on the cell membrane (Matsuura et al. 2019). The fusion peptide mediates fusion of the viral envelop with the cell membrane (Meher and Chakraborty 2020).	Retroviridae	Env protein of bovine leukemia virus