Biology:Syncytin-1

From HandWiki
Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Syncytin-1 also known as enverin is a protein found in humans and other primates that is encoded by the ERVW-1 gene (endogenous retrovirus group W envelope member 1). Syncytin-1 is a cell-cell fusion protein whose function is best characterized in placental development.[1][2] The placenta in turn aids in embryo attachment to the uterus and establishment of a nutrient supply.

The gene encoding this protein is an endogenous retroviral element that is the remnant of an ancient retroviral infection integrated into the primate germ line. In the case of syncytin-1 (which is found in humans, apes, and Old World but not New World monkeys), this integration likely occurred more than 25 million years ago.[3] Syncytin-1 is one of two known syncytin proteins expressed in catarrhini primates (the other being syncytin-2) and one of many viral genomes incorporated on multiple occasions over evolutionary time in diverse mammalian species.[4]

ERVW-1 is located within ERVWE1,[5][6] a full length provirus on chromosome 7 at locus 7q21.2 flanked by long terminal repeats (LTRs) and is preceded by ERVW1 gag (Group AntiGen) and pol (POLymerase) within the provirus, both of which contain nonsense mutations rendering them non-coding.[7][8]

Syncytin-1 is also implicated in a number of neurological pathologies, most notably, multiple sclerosis, as an immunogen.

Placental development

Syncytin-1 mediated trophoblast fusion is essential for normal placental development. The early placental barrier is composed of two placenta specific cell layers: cytotrophoblast and syncytiotrophoblast layer. Cytotrophoblasts are continually dividing, non-differentiated cells and the syncytiotrophoblast is one, fully differentiated, non dividing, fused cell syncytium. Syncytin-1 expression on the surface of cytotrophoblasts and syncytiotrophoblast mediate fusion. The syncytiotrophoblast layer is the interface between the developing fetus and the maternal blood supply, which forms, together with the underlying basal membrane and the fetal endothelium the placental barrier. The placental barrier enables nutrient and waste exchange, while blocking maternal immune and other cells, particles and molecules from passing into the fetal blood circulation. Cytotrophoblasts are forced into senescence by fusion into the syncytiotrophoblast.[9] Therefore, cytotrophoblast proliferation is necessary for growth and maintenance of the syncytiotrophoblast layer. Syncytin-1 expression in cytotrophoblasts promotes G1/S transition and proliferation thereby ensuring continual replenishment of the cytotrophoblast pool.[10] The name syncytin derives from its involvement in the formation of syncytium, the multinucleated syncytiotrophoblast protoplasm. There is another endogenous retroviral envelope protein expressed in the placenta from a different ERV family: syncytin-2 (of HERV-FRD).

Receptor

The syncytin-1 receptor is the Na-dependent amino acid transporter 2 (ASCT2 or SLC1A5).[11][12] This receptor places syncytin-1 in a large viral interference group called retroviral mammalian type D receptor (RDR) interference group.[13] Syncytin-1 has been shown to interfere with viral infection in-vitro by RDR interference group member spleen necrosis virus.[14] Syncytin-1 can also recognize ASCT1 or SLC1A4, but this receptor is not a receptor for the RDR interference group. Mutation studies of syncytin-1 and of ASCT2 have provided insight into potential receptor binding domains and determinants. A putative receptor binding domain was identified in syncytin-1 at residues 117-144.[15] The amino acid sequence at this region is well conserved amongst RDR interference group members. The motif SDGGGX2DX2R is present in all RDR interference group members within this conserved region and may play an important role in binding. Preliminary evidence with syncytin-1 and spleen necrosis virus indicate this motif contains the ASCT2 binding determinants.[15][16][17]

The largest ectodomain of ASCT1 and ASCT2, extracellular loop 2 (ECL2), contains at its C-terminus a 21 residue hypervariable region between human, mouse, and hamster receptors. This region was shown to confer specificity to receptor binding by most RDR interference group members.[18] Both glycosylation pattern and amino acid sequence differences between human and rodent receptors are determinants in susceptibility to infection by RDR interference group members. Murine (mouse) ASCT1 expressing cells are only susceptible to syncytin-1 and another endogenous retroviral env protein (that of Baboon Endogenous Retrovirus) and human ASCT1 has only been shown to bind syncytin-1.[18] Further research is needed to elucidate ASCT and RDR binding determinants.

Structure

Syncytin-1 shares many structural elements with class I retroviral glycoproteins (such as, Murine Leukemia Virus gp, and HIV gp120, gp41). It is composed of a surface subunit (SU) and transmembrane subunit (TM), separated by a furin cleavage site.[6] The two subunits form a heterodimer and are likely linked by a disulfide bond between two conserved cysteine rich motifs: CXXC in SU and CX6CC in TM.[6] This heterodimer likely forms a homotrimer at the cell surface. Syncytin-1 TM contains the fusion peptide, and two heptad repeats separated by a chain reversal region common to class I retroviral glycoproteins. Syncytin-1 is a single pass membrane protein and has a relatively long cytoplasmic tail; however, truncation of the cytoplasmic tail to just 14 residues has been shown to increase fusogenic activity, indicating its C-terminus is likely involved in modulating fusion activity.[19]

Clinical significance

Pre-eclampsia

Hypoxic conditions characteristic of Pre-eclampsia and IUGR are associated with abnormal expression of syncytin-1 in trophoblast cells[20] and pre-eclamptic placental tissue has reduced levels of syncytin-1 expression.[21] Abnormal syncytin-1 expression likely plays an important role in placental pathologies.

Neurological pathologies

ERVW-1 is a single locus within the HERV-W family encoding a fully functional env protein. mRNA and protein expression of the ERVW-1 locus in neural tissue is implicated in neurodegeneration and development of multiple sclerosis. Multiple sclerosis retrovirus like particle (MSRV) envelope protein shares high sequence similarity to ERVW-1 encoded syncytin-1 and has long been studied as an important factor in MS pathogenesis.[22] The gene locus of MSRV env has not been determined.

Preliminary evidence implicates aberrant expression of ERVW-1 in neuron and glial cells and HERV-W LTR mediated aberrant cellular protein expression in the pathogenesis of bipolar disorder and schizophrenia.[15][23]

References

  1. ↑ "From ancestral infectious retroviruses to bona fide cellular genes: role of the captured syncytins in placentation". Placenta 33 (9): 663–71. September 2012. doi:10.1016/j.placenta.2012.05.005. PMID 22695103. 
  2. ↑ "The role of syncytins in human reproduction and reproductive organ cancers". Reproduction 152 (5): R167–78. 2016. doi:10.1530/REP-16-0031. PMID 27486264. 
  3. ↑ "Phylogeny of a novel family of human endogenous retrovirus sequences, HERV-W, in humans and other primates". AIDS Research and Human Retroviruses 15 (17): 1529–33. November 1999. doi:10.1089/088922299309810. PMID 10580403. 
  4. ↑ "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): 20120507. September 2013. doi:10.1098/rstb.2012.0507. PMID 23938756. 
  5. ↑ "The endogenous retroviral locus ERVWE1 is a bona fide gene involved in hominoid placental physiology". Proceedings of the National Academy of Sciences of the United States of America 101 (6): 1731–6. 2004. doi:10.1073/pnas.0305763101. PMID 14757826. Bibcode: 2004PNAS..101.1731M. 
  6. ↑ 6.0 6.1 6.2 "Synthesis, assembly, and processing of the Env ERVWE1/syncytin human endogenous retroviral envelope". Journal of Virology 79 (9): 5585–93. May 2005. doi:10.1128/JVI.79.9.5585-5593.2005. PMID 15827173. 
  7. ↑ "ERVW-1 endogenous retrovirus group W member 1 [Homo sapiens (human)"]. Gene - NCBI. https://www.ncbi.nlm.nih.gov/gene/30816. 
  8. ↑ "Chromosomal distribution and coding capacity of the human endogenous retrovirus HERV-W family". AIDS Research and Human Retroviruses 16 (8): 731–40. May 2000. doi:10.1089/088922200308738. PMID 10826480. 
  9. ↑ "Cell fusion induced by ERVWE1 or measles virus causes cellular senescence". Genes & Development 27 (21): 2356–66. November 2013. doi:10.1101/gad.227512.113. PMID 24186980. 
  10. ↑ "Syncytin-1 modulates placental trophoblast cell proliferation by promoting G1/S transition". Cellular Signalling 25 (4): 1027–35. April 2013. doi:10.1016/j.cellsig.2013.01.008. PMID 23333240. 
  11. ↑ "The envelope glycoprotein of human endogenous retrovirus type W uses a divergent family of amino acid transporters/cell surface receptors". Journal of Virology 76 (13): 6442–52. July 2002. doi:10.1128/JVI.76.13.6442-6452.2002. PMID 12050356. 
  12. ↑ "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". Journal of Virology 74 (7): 3321–9. April 2000. doi:10.1128/jvi.74.7.3321-3329.2000. PMID 10708449. 
  13. ↑ "Receptor interference groups of 20 retroviruses plating on human cells". Virology 176 (1): 58–69. May 1990. doi:10.1016/0042-6822(90)90230-O. PMID 1691887. 
  14. ↑ "The envelope glycoprotein of human endogenous retrovirus HERV-W induces cellular resistance to spleen necrosis virus" (in en). Archives of Virology 148 (4): 659–75. April 2003. doi:10.1007/s00705-002-0960-x. PMID 12664292. 
  15. ↑ 15.0 15.1 15.2 "Human Endogenous Retroviruses as Pathogenic Factors in the Development of Schizophrenia". Frontiers in Psychiatry 6: 183. January 2015. doi:10.3389/fpsyt.2015.00183. PMID 26793126. 
  16. ↑ "Mapping of receptor binding domains in the envelope protein of spleen necrosis virus". Journal of Virology 69 (7): 4339–46. July 1995. doi:10.1128/JVI.69.7.4339-4346.1995. PMID 7769695. 
  17. ↑ "Mutational analysis of the envelope protein of spleen necrosis virus". Journal of Virology 70 (9): 6036–43. September 1996. doi:10.1128/JVI.70.9.6036-6043.1996. PMID 8709226. 
  18. ↑ 18.0 18.1 "N-linked glycosylation and sequence changes in a critical negative control region of the ASCT1 and ASCT2 neutral amino acid transporters determine their retroviral receptor functions". Journal of Virology 77 (5): 2936–45. March 2003. doi:10.1128/JVI.77.5.2936-2945.2003. PMID 12584318. 
  19. ↑ "C-Terminal truncations of syncytin-1 (ERVWE1 envelope) that increase its fusogenicity". Biological Chemistry 387 (8): 1113–20. August 2006. doi:10.1515/BC.2006.137. PMID 16895482. 
  20. ↑ "Syncytin-1 and glial cells missing a: hypoxia-induced deregulated gene expression along with disordered cell fusion in primary term human trophoblasts". Gynecologic and Obstetric Investigation 68 (1): 9–18. 2009-01-01. doi:10.1159/000209396. PMID 19321927. https://opus4.kobv.de/opus4-fau/files/3181/goi2009068001009.pdf. 
  21. ↑ "Syncytin 1 in the human placenta". Placenta 33 (6): 460–6. June 2012. doi:10.1016/j.placenta.2012.02.012. PMID 22381536. 
  22. ↑ "Analysis of transcribed human endogenous retrovirus W env loci clarifies the origin of multiple sclerosis-associated retrovirus env sequences". Retrovirology 6: 37. April 2009. doi:10.1186/1742-4690-6-37. PMID 19368703. 
  23. ↑ "HERV-W-related RNA detected in plasma from individuals with recent-onset schizophrenia or schizoaffective disorder". Molecular Psychiatry 9 (1): 12–3. January 2004. doi:10.1038/sj.mp.4001439. PMID 14571258. 

External links

  • ERVW-1 on the Atlas of Genetics and Oncology



Retrieved from "https://handwiki.org/wiki/index.php?title=Biology:Syncytin-1&oldid=3583081"