Syncytin-1

Last updated
ERVW-1
Identifiers
Aliases ERVW-1 , ENV, ENVW, ERVWE1, HERV-7q, HERV-W-ENV, HERV7Q, HERVW, HERVWENV, endogenous retrovirus group W member 1, endogenous retrovirus group W member 1, envelope
External IDs OMIM: 604659 HomoloGene: 137309 GeneCards: ERVW-1
Orthologs
SpeciesHumanMouse
Entrez

30816

n/a

Ensembl

ENSG00000242950

n/a

UniProt

Q9UQF0

n/a

RefSeq (mRNA)

NM_014590
NM_001130925

n/a

RefSeq (protein)

NP_001124397
NP_055405

n/a

Location (UCSC) Chr 7: 92.47 – 92.48 Mb n/a
PubMed search [2] n/a
Wikidata
View/Edit Human

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. [3] [4] The placenta in turn aids in embryo attachment to the uterus and establishment of a nutrient supply.

Contents

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. [5] 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. [6]

ERVW-1 is located within ERVWE1, [7] [8] 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. [9] [10]

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. [11] 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. [12] 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). [13] [14] This receptor places syncytin-1 in a large viral interference group called retroviral mammalian type D receptor (RDR) interference group. [15] Syncytin-1 has been shown to interfere with viral infection in-vitro by RDR interference group member spleen necrosis virus. [16] 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. [17] 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. [17] [18] [19]

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. [20] 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. [20] 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. [8] 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. [8] 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. [21]

Clinical significance

Pre-eclampsia

Hypoxic conditions characteristic of Pre-eclampsia and IUGR are associated with abnormal expression of syncytin-1 in trophoblast cells [22] and pre-eclamptic placental tissue has reduced levels of syncytin-1 expression. [23] 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. [24] 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. [17] [25]

Related Research Articles

<span class="mw-page-title-main">Retrovirus</span> Family of viruses

A retrovirus is a type of virus that inserts a DNA copy of its RNA genome into the DNA of a host cell that it invades, thus changing the genome of that cell. Once inside the host cell's cytoplasm, the virus uses its own reverse transcriptase enzyme to produce DNA from its RNA genome, the reverse of the usual pattern, thus retro (backwards). The new DNA is then incorporated into the host cell genome by an integrase enzyme, at which point the retroviral DNA is referred to as a provirus. The host cell then treats the viral DNA as part of its own genome, transcribing and translating the viral genes along with the cell's own genes, producing the proteins required to assemble new copies of the virus. Many retroviruses cause serious diseases in humans, other mammals, and birds.

<span class="mw-page-title-main">Placenta</span> Organ that connects the fetus to the uterine wall

The placenta is a temporary embryonic and later fetal organ that begins developing from the blastocyst shortly after implantation. It plays critical roles in facilitating nutrient, gas and waste exchange between the physically separate maternal and fetal circulations, and is an important endocrine organ, producing hormones that regulate both maternal and fetal physiology during pregnancy. The placenta connects to the fetus via the umbilical cord, and on the opposite aspect to the maternal uterus in a species-dependent manner. In humans, a thin layer of maternal decidual (endometrial) tissue comes away with the placenta when it is expelled from the uterus following birth. Placentas are a defining characteristic of placental mammals, but are also found in marsupials and some non-mammals with varying levels of development.

<i>Gammaretrovirus</i> Genus of viruses

Gammaretrovirus is a genus in the Retroviridae family. Example species are the murine leukemia virus and the feline leukemia virus. They cause various sarcomas, leukemias and immune deficiencies in mammals, reptiles and birds.

<span class="mw-page-title-main">Endogenous retrovirus</span> Inherited retrovirus encoded in an organisms genome

Endogenous retroviruses (ERVs) are endogenous viral elements in the genome that closely resemble and can be derived from retroviruses. They are abundant in the genomes of jawed vertebrates, and they comprise up to 5–8% of the human genome.

<span class="mw-page-title-main">Syncytiotrophoblast</span> Embryonic cell of the placental surface

Syncytiotrophoblast is the epithelial covering of the highly vascular embryonic placental villi, which invades the wall of the uterus to establish nutrient circulation between the embryo and the mother. It is a multi-nucleate, terminally differentiated syncytium, extending to 13 cm.

<i>Jaagsiekte sheep retrovirus</i> Species of virus

Jaagsiekte sheep retrovirus (JSRV) is a betaretrovirus which is the causative agent of a contagious lung cancer in sheep, called ovine pulmonary adenocarcinoma.

Simian foamy virus (SFV) is a species of the genus Spumavirus that belongs to the family of Retroviridae. It has been identified in a wide variety of primates, including prosimians, New World and Old World monkeys, as well as apes, and each species has been shown to harbor a unique (species-specific) strain of SFV, including African green monkeys, baboons, macaques, and chimpanzees. As it is related to the more well-known retrovirus human immunodeficiency virus (HIV), its discovery in primates has led to some speculation that HIV may have been spread to the human species in Africa through contact with blood from apes, monkeys, and other primates, most likely through bushmeat-hunting practices.

Env is a viral gene that encodes the protein forming the viral envelope. The expression of the env gene enables retroviruses to target and attach to specific cell types, and to infiltrate the target cell membrane.

<span class="mw-page-title-main">ERV3</span> Protein-coding gene in the species Homo sapiens

HERV-R_7q21.2 provirus ancestral envelope (Env) polyprotein is a protein that in humans is encoded by the ERV3 gene.

<span class="mw-page-title-main">Neutral amino acid transporter B(0)</span> Protein-coding gene in the species Homo sapiens

Neutral amino acid transporter B(0) is a protein that in humans is encoded by the SLC1A5 gene.

HERV-K_19q12 provirus ancestral Pol protein is a protein that in humans is encoded by the ERVK6 gene.

<span class="mw-page-title-main">Neutral amino acid transporter A</span> Protein-coding gene in the species Homo sapiens

Neutral amino acid transporter A is a protein that in humans is encoded by the SLC1A4 gene.

<span class="mw-page-title-main">INSL4</span> Protein-coding gene in the species Homo sapiens

Early placenta insulin-like peptide is a protein that in humans is encoded by the INSL4 gene.

<span class="mw-page-title-main">Syncytin-2</span> Protein-coding gene in the species Homo sapiens

Syncytin-2 also known as endogenous retrovirus group FRD member 1 is a protein that in humans is encoded by the ERVFRD-1 gene. This protein plays a key role in the implantation of human embryos in the womb.

Mason-Pfizer monkey virus (M-PMV), formerly Simian retrovirus (SRV), is a species of retroviruses that usually infect and cause a fatal immune deficiency in Asian macaques. The ssRNA virus appears sporadically in mammary carcinoma of captive macaques at breeding facilities which expected as the natural host, but the prevalence of this virus in feral macaques remains unknown. M-PMV was transmitted naturally by virus-containing body fluids, via biting, scratching, grooming, and fighting. Cross contaminated instruments or equipment (fomite) can also spread this virus among animals.

An endogenous viral element (EVE) is a DNA sequence derived from a virus, and present within the germline of a non-viral organism. EVEs may be entire viral genomes (proviruses), or fragments of viral genomes. They arise when a viral DNA sequence becomes integrated into the genome of a germ cell that goes on to produce a viable organism. The newly established EVE can be inherited from one generation to the next as an allele in the host species, and may even reach fixation.

Human endogenous retrovirus K (HERV-K) or Human teratocarcinoma-derived virus (HDTV) is a family of human endogenous retroviruses associated with malignant tumors of the testes. Phylogenetically, the HERV-K group belongs to the ERV2 or Class II or Betaretrovirus-like supergroup. Over the past several years, it has been found that this group of ERVs play an important role in embryogenesis, but their expression is silenced in most cell types in healthy adults. The HERV-K family, and particularly its subgroup HML-2, is the youngest and most transcriptionally active group and hence, it is the best studied among other ERVs. Reactivation of it or anomalous expression of HML-2 in adult tissues has been associated with various types of cancer and with neurodegenerative diseases such as amytrophic lateral sclerosis (ALS). Endogenous retrovirus K (HERV-K) is related to mammary tumor virus in mice. It exists in the human and cercopithecoid genomes. Human genome contains hundreds of copies of HERV-K and many of them possess complete open reading frames (ORFs) that are transcribed and translated, especially in early embryogenesis and in malignancies. HERV-K is also found in apes and Old World monkeys. It is uncertain how long ago in primate evolution the full-length HERV-K proviruses which are in the human genome today were created.

Human Endogenous Retrovirus-W (HERV-W) is the coding for a protein that would normally be part of the envelope of one family of Human Endogenous Retro-Viruses, or HERVs.

<span class="mw-page-title-main">Endogenous retrovirus group V member 2, envelope</span> Protein-coding gene in the species Homo sapiens

Endogenous retrovirus group V member 2, envelope is a protein that in humans is encoded by the ERVV-2 gene.

<span class="mw-page-title-main">Suppressyn</span> Mammalian protein found in Homo sapiens

Suppressyn (SUPYN) is a protein that in humans is encoded by the ERVH48-1 gene.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000242950 - Ensembl, May 2017
  2. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  3. ↑ Dupressoir A, Lavialle C, Heidmann T (September 2012). "From ancestral infectious retroviruses to bona fide cellular genes: role of the captured syncytins in placentation". Placenta. 33 (9): 663–71. doi:10.1016/j.placenta.2012.05.005. PMID   22695103.
  4. ↑ Soygur B, Sati L (2016). "The role of syncytins in human reproduction and reproductive organ cancers". Reproduction. 152 (5): R167–78. doi: 10.1530/REP-16-0031 . PMID   27486264.
  5. ↑ Voisset C, Blancher A, Perron H, Mandrand B, Mallet F, Paranhos-Baccalà G (November 1999). "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. doi:10.1089/088922299309810. PMID   10580403.
  6. ↑ Lavialle C, Cornelis G, Dupressoir A, Esnault C, Heidmann O, Vernochet C, Heidmann T (September 2013). "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. doi:10.1098/rstb.2012.0507. PMC   3758191 . PMID   23938756.
  7. ↑ Mallet F, Bouton O, Prudhomme S, Cheynet V, Oriol G, Bonnaud B, Lucotte G, Duret L, Mandrand B (2004). "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. Bibcode:2004PNAS..101.1731M. doi: 10.1073/pnas.0305763101 . PMC   341840 . PMID   14757826.
  8. 1 2 3 Cheynet V, Ruggieri A, Oriol G, Blond JL, Boson B, Vachot L, Verrier B, Cosset FL, Mallet F (May 2005). "Synthesis, assembly, and processing of the Env ERVWE1/syncytin human endogenous retroviral envelope". Journal of Virology. 79 (9): 5585–93. doi:10.1128/JVI.79.9.5585-5593.2005. PMC   1082723 . PMID   15827173.
  9. ↑ "ERVW-1 endogenous retrovirus group W member 1 [Homo sapiens (human)]". Gene - NCBI. Retrieved 2016-11-23.
  10. ↑ Voisset C, Bouton O, Bedin F, Duret L, Mandrand B, Mallet F, Paranhos-Baccala G (May 2000). "Chromosomal distribution and coding capacity of the human endogenous retrovirus HERV-W family". AIDS Research and Human Retroviruses. 16 (8): 731–40. doi:10.1089/088922200308738. PMID   10826480.
  11. ↑ Chuprin A, Gal H, Biron-Shental T, Biran A, Amiel A, Rozenblatt S, Krizhanovsky V (November 2013). "Cell fusion induced by ERVWE1 or measles virus causes cellular senescence". Genes & Development. 27 (21): 2356–66. doi:10.1101/gad.227512.113. PMC   3828521 . PMID   24186980.
  12. ↑ Huang Q, Li J, Wang F, Oliver MT, Tipton T, Gao Y, Jiang SW (April 2013). "Syncytin-1 modulates placental trophoblast cell proliferation by promoting G1/S transition". Cellular Signalling. 25 (4): 1027–35. doi:10.1016/j.cellsig.2013.01.008. PMC   4644426 . PMID   23333240.
  13. ↑ Lavillette D, Marin M, Ruggieri A, Mallet F, Cosset FL, Kabat D (July 2002). "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. doi:10.1128/JVI.76.13.6442-6452.2002. PMC   136247 . PMID   12050356.
  14. ↑ Blond JL, Lavillette D, Cheynet V, Bouton O, Oriol G, Chapel-Fernandes S, Mandrand B, Mallet F, Cosset FL (April 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". Journal of Virology. 74 (7): 3321–9. doi:10.1128/jvi.74.7.3321-3329.2000. PMC   111833 . PMID   10708449.
  15. ↑ Sommerfelt MA, Weiss RA (May 1990). "Receptor interference groups of 20 retroviruses plating on human cells". Virology. 176 (1): 58–69. doi:10.1016/0042-6822(90)90230-O. PMID   1691887.
  16. ↑ Ponferrada VG, Mauck BS, Wooley DP (April 2003). "The envelope glycoprotein of human endogenous retrovirus HERV-W induces cellular resistance to spleen necrosis virus". Archives of Virology. 148 (4): 659–75. doi:10.1007/s00705-002-0960-x. PMID   12664292. S2CID   9776756.
  17. 1 2 3 Slokar G, Hasler G (January 2015). "Human Endogenous Retroviruses as Pathogenic Factors in the Development of Schizophrenia". Frontiers in Psychiatry. 6: 183. doi: 10.3389/fpsyt.2015.00183 . PMC   4707225 . PMID   26793126.
  18. ↑ Martinez I, Dornburg R (July 1995). "Mapping of receptor binding domains in the envelope protein of spleen necrosis virus". Journal of Virology. 69 (7): 4339–46. doi:10.1128/JVI.69.7.4339-4346.1995. PMC   189174 . PMID   7769695.
  19. ↑ Martinez I, Dornburg R (September 1996). "Mutational analysis of the envelope protein of spleen necrosis virus". Journal of Virology. 70 (9): 6036–43. doi:10.1128/JVI.70.9.6036-6043.1996. PMC   190624 . PMID   8709226.
  20. 1 2 Marin M, Lavillette D, Kelly SM, Kabat D (March 2003). "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. doi:10.1128/JVI.77.5.2936-2945.2003. PMC   149750 . PMID   12584318.
  21. ↑ Drewlo S, Leyting S, Kokozidou M, Mallet F, Pötgens AJ (August 2006). "C-Terminal truncations of syncytin-1 (ERVWE1 envelope) that increase its fusogenicity". Biological Chemistry. 387 (8): 1113–20. doi:10.1515/BC.2006.137. PMID   16895482. S2CID   44993411.
  22. ↑ Wich C, Kausler S, Dotsch J, Rascher W, Knerr I (2009-01-01). "Syncytin-1 and glial cells missing a: hypoxia-induced deregulated gene expression along with disordered cell fusion in primary term human trophoblasts" (PDF). Gynecologic and Obstetric Investigation. 68 (1): 9–18. doi:10.1159/000209396. PMID   19321927. S2CID   207667965.
  23. ↑ Holder BS, Tower CL, Abrahams VM, Aplin JD (June 2012). "Syncytin 1 in the human placenta". Placenta. 33 (6): 460–6. doi:10.1016/j.placenta.2012.02.012. PMID   22381536.
  24. ↑ Laufer G, Mayer J, Mueller BF, Mueller-Lantzsch N, Ruprecht K (April 2009). "Analysis of transcribed human endogenous retrovirus W env loci clarifies the origin of multiple sclerosis-associated retrovirus env sequences". Retrovirology. 6: 37. doi:10.1186/1742-4690-6-37. PMC   2672075 . PMID   19368703.
  25. ↑ Karlsson H, Schröder J, Bachmann S, Bottmer C, Yolken RH (January 2004). "HERV-W-related RNA detected in plasma from individuals with recent-onset schizophrenia or schizoaffective disorder". Molecular Psychiatry. 9 (1): 12–3. doi: 10.1038/sj.mp.4001439 . PMID   14571258.
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