C-Terminal truncations of syncytin-1 (ERVWE1 envelope) that increase its fusogenicity
-
Sascha Drewlo
Abstract
Syncytin-1, the envelope protein of ERVWE1, an endogenous retrovirus of the HERV-W family, plays an important role in regulating fusion of the placental trophoblast. At least one of its receptors is expressed on a variety of human cell types. Its ability to fuse cells makes it an attractive candidate molecule in gene therapy against cancer. We studied the relevance of sequences in the cytoplasmic tail of syncytin-1 for inducing cell-cell fusion. We generated a series of C-terminally truncated syncytin-1 variants. Sequences immediately adjacent to the transmembrane region of syncytin-1 were necessary for inducing optimal fusion, whereas the extreme C-terminus of syncytin-1 partially inhibited its fusogenicity. Two variants of syncytin-1, truncated after residues 483 and 515, were significantly hyperfusogenic compared to wild-type syncytin-1. Cellular and cell-surface expression levels of these two variant proteins were similar to those of wild-type syncytin-1. In testing the latter we found that only a very minor portion of recombinantly expressed cellular syncytin-1 was fully mature and expressed on the cell surface. Our results contribute to the understanding of the structure-function relationship of syncytin-1, and might have implications for the use of this molecule in gene therapy.
References
An, D.S., Xie, Y., and Chen, I.S. (2001). Envelope gene of the human endogenous retrovirus HERV-W encodes a functional retrovirus envelope. J. Virol.75, 3488–3489.10.1128/JVI.75.7.3488-3489.2001Search in Google Scholar
Antony, J.M., van Marle, G., Opii, W., Butterfield, D.A., Mallet, F., Yong, V.W., Wallace, J.L., Deacon, R.M., Warren, K., and Power, C. (2004). Human endogenous retrovirus glycoprotein-mediated induction of redox reactants causes oligodendrocyte death and demyelination. Nat. Neurosci.7, 1088–1095.10.1038/nn1319Search in Google Scholar
Bateman, A.R., Harrington, K.J., Kottke, T., Ahmed, A., Melcher, A.A., Gough, M.J., Linardakis, E., Riddle, D., Dietz, A., Lohse, C.M., et al. (2002). Viral fusogenic membrane glycoproteins kill solid tumor cells by nonapoptotic mechanisms that promote cross presentation of tumor antigens by dendritic cells. Cancer Res.62, 6566–6578.Search in Google Scholar
Blond, J.L., Beseme, F., Duret, L., Bouton, O., Bedin, F., Perron, H., Mandrand, B., and Mallet, F. (1999). Molecular characterization and placental expression of HERV-W, a new human endogenous retrovirus family. J. Virol.73, 1175–1185.10.1128/JVI.73.2.1175-1185.1999Search in Google Scholar
Blond, J.L., Lavillette, D., Cheynet, V., Bouton, O., Oriol, G., Chapel-Fernandes, S., Mandrand, B., Mallet, F., and Cosset, F.L. (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, 3321–3329.10.1128/JVI.74.7.3321-3329.2000Search in Google Scholar
Bobkova, M., Stitz, J., Engelstadter, M., Cichutek, K., and Buchholz, C.J. (2002). Identification of R-peptides in envelope proteins of C-type retroviruses. J. Gen. Virol.83, 2241–2246.10.1099/0022-1317-83-9-2241Search in Google Scholar
Bonnaud, B., Bouton, O., Oriol, G., Cheynet, V., Duret, L., and Mallet, F. (2004). Evidence of selection on the domesticated ERVWE1 env retroviral element involved in placentation. Mol. Biol. Evol.21, 1895–1901.10.1093/molbev/msh206Search in Google Scholar
Borges, M., Bose, P., Frank, H.G., Kaufmann, P., and Potgens, A.J. (2003). A two-colour fluorescence assay for the measurement of syncytial fusion between trophoblast-derived cell lines. Placenta24, 959–964.10.1016/S0143-4004(03)00173-5Search in Google Scholar
Chang, C., Chen, P.T., Chang, G.D., Huang, C.J., and Chen, H. (2004). Functional characterization of the placental fusogenic membrane protein syncytin. Biol. Reprod.71, 1956–1962.10.1095/biolreprod.104.033340Search in Google Scholar PubMed
Cheynet, V., Ruggieri, A., Oriol, G., Blond, J.L., Boson, B., Vachot, L., Verrier, B., Cosset, F.L., and Mallet, F. (2005). Synthesis, assembly, and processing of the Env ERVWE1/syncytin human endogenous retroviral envelope. J. Virol.79, 5585–5593.10.1128/JVI.79.9.5585-5593.2005Search in Google Scholar PubMed PubMed Central
Frendo, J.L., Olivier, D., Cheynet, V., Blond, J.L., Bouton, O., Vidaud, M., Rabreau, M., Evain-Brion, D., and Mallet, F. (2003). Direct involvement of HERV-W Env glycoprotein in human trophoblast cell fusion and differentiation. Mol. Cell. Biol.23, 3566–3574.10.1128/MCB.23.10.3566-3574.2003Search in Google Scholar PubMed PubMed Central
Galanis, E., Bateman, A., Johnson, K., Diaz, R.M., James, C.D., Vile, R., and Russell, S.J. (2001). Use of viral fusogenic membrane glycoproteins as novel therapeutic transgenes in gliomas. Hum. Gene Ther.12, 811–821.10.1089/104303401750148766Search in Google Scholar PubMed
Green, B.J., Lee, C.S., and Rasko, J.E. (2004). Biodistribution of the RD114/mammalian type D retrovirus receptor, RDR. J. Gene Med.6, 249–259.10.1002/jgm.517Search in Google Scholar PubMed
Higuchi, H., Bronk, S.F., Bateman, A., Harrington, K., Vile, R.G., and Gores, G.J. (2000). Viral fusogenic membrane glycoprotein expression causes syncytia formation with bioenergetic cell death: implications for gene therapy. Cancer Res.60, 6396–6402.Search in Google Scholar
Lavillette, D., Marin, M., Ruggieri, A., Mallet, F., Cosset, F.L., and Kabat, D. (2002). The envelope glycoprotein of human endogenous retrovirus type W uses a divergent family of amino acid transporters/cell surface receptors. J. Virol.76, 6442–6452.10.1128/JVI.76.13.6442-6452.2002Search in Google Scholar PubMed PubMed Central
Mallet, F., Bouton, O., Prudhomme, S., Cheynet, V., Oriol, G., Bonnaud, B., Lucotte, G., Duret, L., and Mandrand, B. (2004). The endogenous retroviral locus ERVWE1 is a bona fide gene involved in hominoid placental physiology. Proc. Natl. Acad. Sci. USA101, 1731–1736.10.1073/pnas.0305763101Search in Google Scholar PubMed PubMed Central
Mi, S., Lee, X., Li, X., Veldman, G.M., Finnerty, H., Racie, L., LaVallie, E., Tang, X.Y., Edouard, P., Howes, S., et al. (2000). Syncytin is a captive retroviral envelope protein involved in human placental morphogenesis. Nature403, 785–789.10.1038/35001608Search in Google Scholar PubMed
Ponferrada, V.G., Mauck, B.S., and Wooley, D.P. (2003). The envelope glycoprotein of human endogenous retrovirus HERV-W induces cellular resistance to spleen necrosis virus. Arch. Virol.148, 659–675.10.1007/s00705-002-0960-xSearch in Google Scholar PubMed
Rasko, J.E., Battini, J.L., Gottschalk, R.J., Mazo, I., and Miller, A.D. (1999). The RD114/simian type D retrovirus receptor is a neutral amino acid transporter. Proc. Natl. Acad. Sci. USA96, 2129–2134.10.1073/pnas.96.5.2129Search in Google Scholar PubMed PubMed Central
Rote, N.S., Chakrabarti, S., and Stetzer, B.P. (2004). The role of human endogenous retroviruses in trophoblast differentiation and placental development. Placenta25, 673–683.10.1016/j.placenta.2004.02.008Search in Google Scholar PubMed
Tailor, C.S., Nouri, A., Zhao, Y., Takeuchi, Y., and Kabat, D. (1999). A sodium-dependent neutral-amino-acid transporter mediates infections of feline and baboon endogenous retroviruses and simian type D retroviruses. J. Virol.73, 4470–4474.10.1128/JVI.73.5.4470-4474.1999Search in Google Scholar PubMed PubMed Central
Yang, C. and Compans, R.W. (1996). Analysis of the cell fusion activities of chimeric simian immunodeficiency virus-murine leukemia virus envelope proteins: inhibitory effects of the R peptide. J. Virol.70, 248–254.10.1128/jvi.70.1.248-254.1996Search in Google Scholar PubMed PubMed Central
Yang, C. and Compans, R.W. (1997). Analysis of the murine leukemia virus R peptide: delineation of the molecular determinants which are important for its fusion inhibition activity. J. Virol.71, 8490–8496.10.1128/jvi.71.11.8490-8496.1997Search in Google Scholar
©2006 by Walter de Gruyter Berlin New York
Articles in the same Issue
- Caspase-containing complexes in the regulation of cell death and inflammation
- Regulation of human cathepsin B by alternative mRNA splicing: homeostasis, fatal errors and cell death
- The peptidases from fungi and viruses
- C. elegans as a model system to study the function of the COG complex in animal development
- Functional responses of bone cells to thrombin
- Homologous substitution of ACE C-domain regions with N-domain sequences: effect on processing, shedding, and catalytic properties
- Production and processing of a recombinant Fasciola hepatica cathepsin B-like enzyme (FhcatB1) reveals potential processing mechanisms in the parasite
- Development of a red-shifted fluorescence-based assay for SARS-coronavirus 3CL protease: identification of a novel class of anti-SARS agents from the tropical marine sponge Axinella corrugata
- Single-cell resolution imaging of membrane-anchored hepatitis C virus NS3/4A protease activity
- Treatment of MCF-7 cells with taxol and etoposide induces distinct alterations in the expression of apoptosis-related genes BCL2, BCL2L12, BAX, CASPASE-9 and FAS
- Proteolytic mechanism of a novel mitochondrial and chloroplastic PreP peptidasome
- Tripeptidyl-peptidase I in health and disease
- Molecular and functional analysis of new members of the wheat PR4 gene family
- C-Terminal truncations of syncytin-1 (ERVWE1 envelope) that increase its fusogenicity
- Disease processes may be reflected by correlations among tissue kallikrein proteases but not with proteolytic factors uPA and PAI-1 in primary ovarian carcinoma
- Heparin modulation of human plasma kallikrein on different substrates and inhibitors
- Adaptation of the behaviour of an aspartic proteinase inhibitor by relocation of a lysine residue by one helical turn
- Cathepsins L and S are not required for activation of dipeptidyl peptidase I (cathepsin C) in mice
Articles in the same Issue
- Caspase-containing complexes in the regulation of cell death and inflammation
- Regulation of human cathepsin B by alternative mRNA splicing: homeostasis, fatal errors and cell death
- The peptidases from fungi and viruses
- C. elegans as a model system to study the function of the COG complex in animal development
- Functional responses of bone cells to thrombin
- Homologous substitution of ACE C-domain regions with N-domain sequences: effect on processing, shedding, and catalytic properties
- Production and processing of a recombinant Fasciola hepatica cathepsin B-like enzyme (FhcatB1) reveals potential processing mechanisms in the parasite
- Development of a red-shifted fluorescence-based assay for SARS-coronavirus 3CL protease: identification of a novel class of anti-SARS agents from the tropical marine sponge Axinella corrugata
- Single-cell resolution imaging of membrane-anchored hepatitis C virus NS3/4A protease activity
- Treatment of MCF-7 cells with taxol and etoposide induces distinct alterations in the expression of apoptosis-related genes BCL2, BCL2L12, BAX, CASPASE-9 and FAS
- Proteolytic mechanism of a novel mitochondrial and chloroplastic PreP peptidasome
- Tripeptidyl-peptidase I in health and disease
- Molecular and functional analysis of new members of the wheat PR4 gene family
- C-Terminal truncations of syncytin-1 (ERVWE1 envelope) that increase its fusogenicity
- Disease processes may be reflected by correlations among tissue kallikrein proteases but not with proteolytic factors uPA and PAI-1 in primary ovarian carcinoma
- Heparin modulation of human plasma kallikrein on different substrates and inhibitors
- Adaptation of the behaviour of an aspartic proteinase inhibitor by relocation of a lysine residue by one helical turn
- Cathepsins L and S are not required for activation of dipeptidyl peptidase I (cathepsin C) in mice
