Biology:Syncytin-2

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Syncytin-2 also known as endogenous retrovirus group FRD member 1 is a protein that in humans is encoded by ERVFRD-1 gene. It is a member of the HERV-FRD family of endogenous retroviral elements.[1][2] The human ERVFRD-1 gene is located on chromosome 6.[3] Both Syncytin-2 and Syncytin-1 are encoded by ENV genes and were first identified in a human placenta.[4] Specifically, Syncytin-2 was observed in the cytoplasmic membrane of primary trophoblast cells in the placenta.[2]

The receptor for this fusogenic env protein is ASCT-2 and the transporter is MFSD-2.[5][6] In studies conducted that observed the protein interactions with this receptor, it was additionally found that Syncytin-2 signals were detected at the membrane.[2] This is a place of cell-to-cell contact where this protein can interact with its receptor, in order to be able to induce fusion.[2]

General Genomic Structure of HERVs

Structure

Syncytin-2 consists of a crystal structure and forms a post-fusion 6-helix bundle structure.[7][8] It encodes a 59kDa polypeptide, and shares similar structural organization in present-day retroviral envelopes.[8] This protein also has a cleavage site that is used to separate the surface and the transmembrane proteins.[9] The surface subunit binds to an unidentified receptor on the transmembrane subunit of a target cell.[8] In this transmembrane subunit, it consists of an N-terminal fusion peptide, an ectodomain including a leucine zipper motif, a highly hydrophobic transmembrane anchor, and a C-terminal intracellular domain.[8]

In both Syncytin-2 and Syncytin-1, in their structures, the env gene is complete and able to encode for fusogenic activity, but their gag and pol genes are disrupted.[8] In this case, the gag and pol genes serve to accumulate inhibitory mutations in order to allow the gag gene to encode for structural viral proteins and for the pol gene to encode for viral enzymes.[10] While env genes, due to their fusogenic activity, are now used for reproduction and placentation benefits.[10]

Function

The role of this protein is key in the implantation of human embryos in the womb, placental formation, syncytium formation, possibly apoptosis, and the regulation of syncytiotrophoblast creation.[2][11][9]

Syncytins as a whole are primarily expressed in the placenta and the formation of syncytium is conducted by syncytin one and two, with their genes primarily being expressed in trophoblasts.[2] Their fusogenic activity, which originally served to favor cell fusion of a virus, now serves to develop the placental syncytiotrophoblast.[2]

In regard to the regulation of syncytiotrophoblast regulation, the role of Syncytin-2 has not been definitively defined especially for the early phases of placental development, however, this protein is the most serious candidate in comparison to Syncytin-1.[2][12] Through research conducted on this protein, due to the fact that it is only expressed in placental tissue, as well as having a good fusogenic capacity, speculation is pointing to this protein playing a significant role in this regulation earlier on in the developmental process.[12]

Clinical significance

In addition, this class of proteins have been found to potentially or actually be involved in the pathogenesis of diseases such as preeclampsia, tumorigenesis, gestational trophoblastic disease, multiple sclerosis, and gestational diabetes.[2]

There has been research that demonstrates that lower levels of syncytin gene expression and the pathogenesis of preeclampsia may be correlated.[2] For Syncytin-2 in particular, there is a reduced amount of gene expression for this protein in pregnant women with preeclampsia compared to those who were healthy.[2] However, there is no exact role established in the pathogenesis of preeclampsia for syncytins, and most data so far is correlative or hypothetical.

Similarly, the exact influence of syncytins in tumorigenesis is also uncertain, but it is hypothesized that the tumor development may persist due to their fusogenecity.[2]

Additionally, there have been studies that support that Syncytin-2 can also suppress the function of T cells, which can weaken the immune response and increase risks and symptoms associated with infection and disease.[13][14]

Further studies need to be conducted for multiple sclerosis and gestational diabetes, as well as these other diseases to either fully confirm their association or deny those with less research or potentially inaccurate hypothesis.[2]

Evolution

This gene is conserved among all primates, with an estimated age of 45 million years, and entered the primate genome before Syncytin-1.[4] Specifically, this protein entered the genome before the split between New World and Old-World Monkeys.[12] However, this protein is absent in prosimians.[8] Due to its open reading frame, low mutation rate, and a low level of polymorphism among humans, this gene has persisted consistent with its role as a carbohydrate transporter.[15][16] Indicating its significance in mammalian evolution and the potential benefits to reproductive functions given this conservation.[4]

The mouse syncytins are not true orthologues.[17] In mice, they are syncytin-A and syncytin-B, and are unrelated to the human syncytin one and two, and entered the lineage 20 million plus years ago.[5] Mice and rat MFSD-2 can not mediate membrane fusion, which further attests to why they are not true orthologues due to these genes that were co-opted during its evolution.[16] However, because of their similar functions, it is hypothesized that the capture of these retroviral envelope genes, could have potentially played as a factor in the emergence of placental mammals altogether.[18]

The virus, along with some very similar insertions, belong to a group under the Gammaretrovirus-like class I ERVs. Similar ERVs are found in artiodactyls, a result of an independent integration event.[19] A proposed nomenclature suggests putting all such "class I" elements in a genus-level taxon separate from Gammaretrovirus.[20]

References

  1. ↑ "Entrez Gene: HERV-FRD HERV-FRD provirus ancestral Env polyprotein". https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=405754. 
  2. ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 2.12 "Syncytin-1, syncytin-2 and suppressyn in human health and disease". Journal of Molecular Medicine 101 (12): 1527–1542. December 2023. doi:10.1007/s00109-023-02385-6. PMID 37855856. 
  3. ↑ "ERVFRD-1 endogenous retrovirus group FRD member 1, envelope [Homo sapiens (human) - Gene - NCBI"]. https://www.ncbi.nlm.nih.gov/gene/405754#genomic-context. 
  4. ↑ 4.0 4.1 4.2 "The role of syncytins in human reproduction and reproductive organ cancers". Reproduction 152 (5): R167–R178. November 2016. doi:10.1530/rep-16-0031. PMID 27486264. 
  5. ↑ 5.0 5.1 Coquin Y, Ferrand M, Seye A, Menu L, Galy A (24 October 2019). "Syncytins enable novel possibilities to transduce human or mouse primary B cells and to achieve well-tolerated in vivo gene transfer". bioRxiv 10.1101/816223.
  6. ↑ "The Human SLC1A5 (ASCT2) Amino Acid Transporter: From Function to Structure and Role in Cell Biology". Frontiers in Cell and Developmental Biology 6. 2018. doi:10.3389/fcell.2018.00096. PMID 30234109. 
  7. ↑ "X-ray Structures of the Post-fusion 6-Helix Bundle of the Human Syncytins and their Functional Implications". Journal of Molecular Biology 431 (24): 4922–4940. December 2019. doi:10.1016/j.jmb.2019.10.020. PMID 31711961. 
  8. ↑ 8.0 8.1 8.2 8.3 8.4 8.5 "Crystal structure of a pivotal domain of human syncytin-2, a 40 million years old endogenous retrovirus fusogenic envelope gene captured by primates". Journal of Molecular Biology 352 (5): 1029–1034. October 2005. doi:10.1016/j.jmb.2005.07.058. PMID 16140326. 
  9. ↑ 9.0 9.1 "ERVFRD-1 - endogenous retrovirus group FRD member 1, envelope (human)" (in en). PubChem. U.S. National Library of Medicine. https://pubchem.ncbi.nlm.nih.gov/gene/ERVFRD-1/human. 
  10. ↑ 10.0 10.1 Cardoso RM. SYNCYTINS Retroviral proteins with potential role in the development of drug delivery systems (PDF) (Masters thesis). Utrecht University.‌
  11. ↑ "Syncytin-2 plays an important role in the fusion of human trophoblast cells". Journal of Molecular Biology 392 (2): 301–318. September 2009. doi:10.1016/j.jmb.2009.07.025. PMID 19616006. 
  12. ↑ 12.0 12.1 12.2 "Expression of the fusogenic HERV-FRD Env glycoprotein (syncytin 2) in human placenta is restricted to villous cytotrophoblastic cells". Placenta 28 (2–3): 185–191. 2007-02-01. doi:10.1016/j.placenta.2006.03.001. PMID 16714059. https://inserm.hal.science/inserm-00000051. 
  13. ↑ "Exaptation of Retroviral Syncytin for Development of Syncytialized Placenta, Its Limited Homology to the SARS-CoV-2 Spike Protein and Arguments against Disturbing Narrative in the Context of COVID-19 Vaccination". Biology 10 (3): 238. March 2021. doi:10.3390/biology10030238. PMID 33808658. 
  14. ↑ "Energizing the immune army: T cell exhaustion explained | Penn Medicine". https://www.pennmedicine.org/news/t-cell-exhaustion-explained. 
  15. ↑ "Exaptation of Retroviral Syncytin for Development of Syncytialized Placenta, Its Limited Homology to the SARS-CoV-2 Spike Protein and Arguments against Disturbing Narrative in the Context of COVID-19 Vaccination". Biology 10 (3): 238. 2021. doi:10.3390/biology10030238. PMID 33808658. 
  16. ↑ 16.0 16.1 "A placenta-specific receptor for the fusogenic, endogenous retrovirus-derived, human syncytin-2". Proceedings of the National Academy of Sciences of the United States of America 105 (45): 17532–17537. November 2008. doi:10.1073/pnas.0807413105. PMID 18988732. Bibcode: 2008PNAS..10517532E. 
  17. ↑ "Paleovirology of 'syncytins', retroviral env genes exapted for a role in placentation". Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences 368 (1626). September 2013. doi:10.1098/rstb.2012.0507. PMID 23938756. 
  18. ↑ "Human endogenous retroviruses in development and disease". Computational and Structural Biotechnology Journal 19: 5978–5986. 2021-01-01. doi:10.1016/j.csbj.2021.10.037. PMID 34849202. 
  19. ↑ "Classification and characterization of human endogenous retroviruses; mosaic forms are common". Retrovirology 13. January 2016. doi:10.1186/s12977-015-0232-y. PMID 26800882. 
  20. ↑ "Nomenclature for endogenous retrovirus (ERV) loci". Retrovirology 15 (1). August 2018. doi:10.1186/s12977-018-0442-1. PMID 30153831. 

Further reading



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