Syncytin-1 also known as enverin is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

found in humans and other primates that is encoded by the ERVW-1

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

( endogenous retrovirus group W envelope member 1). Syncytin-1 is a cell-cell fusion protein whose function is best characterized in placental development. The placenta in turn aids in

embryo An embryo ( ) is the initial stage of development for a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male sp ...

attachment to the

uterus The uterus (from Latin ''uterus'', : uteri or uteruses) or womb () is the hollow organ, organ in the reproductive system of most female mammals, including humans, that accommodates the embryonic development, embryonic and prenatal development, f ...

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 The "Old World" () is a term for Afro-Eurasia coined by Europeans after 1493, when they became aware of the existence of the Americas. It is used to contrast the continents of Africa, Europe, and Asia in the Eastern Hemisphere, previously ...

but not

New World monkey New World monkeys are the five families of primates that are found in the tropical regions of Mexico, Central and South America: Callitrichidae, Cebidae, Aotidae, Pitheciidae, and Atelidae. The five families are ranked together as the Ceboi ...

s), this integration likely occurred more than 25 million years ago. Syncytin-1 is one of two known syncytin proteins expressed in

catarrhini The parvorder Catarrhini (known commonly as catarrhine monkeys, Old World anthropoids, or Old World monkeys) consists of the Cercopithecoidea and apes (Hominoidea). In 1812, Geoffroy grouped those two groups together and established the name ...

primates (the other being syncytin-2) and one of many viral genomes incorporated on multiple occasions over evolutionary time in diverse mammalian species. ERVW-1 is located within ERVWE1, a full length

provirus A provirus is a virus genome that is integrated into the DNA of a host cell. In the case of bacterial viruses (bacteriophages), proviruses are often referred to as prophages. However, proviruses are distinctly different from prophages and these te ...

on chromosome 7 at locus 7q21.2 flanked by

long terminal repeat A long terminal repeat (LTR) is a pair of identical sequences of DNA, several hundred base pairs long, which occur in eukaryotic genomes on either end of a series of genes or pseudogenes that form a retrotransposon or an endogenous retrovirus o ...

s (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. Syncytin-1 is also implicated in a number of neurological pathologies, most notably,

multiple sclerosis Multiple sclerosis (MS) is an autoimmune disease resulting in damage to myelinthe insulating covers of nerve cellsin the brain and spinal cord. As a demyelinating disease, MS disrupts the nervous system's ability to Action potential, transmit ...

, as an

immunogen An immunogen is any substance that generates B-cell (humoral/antibody) and/or T-cell (cellular) adaptive immune responses upon exposure to a host organism. Immunogens that generate antibodies are called antigens ("antibody-generating"). Immunoge ...

Placental development

Syncytin-1 mediated

trophoblast The trophoblast (from Greek language, Greek : to feed; and : germinator) is the outer layer of cells of the blastocyst. Trophoblasts are present four days after Human fertilization, fertilization in humans. They provide nutrients to the embryo an ...

fusion is essential for normal

placenta The placenta (: placentas or placentae) 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 ...

l 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 A syncytium (; : syncytia; from Greek: σύν ''syn'' "together" and κύτος ''kytos'' "box, i.e. cell") or symplasm is a multinucleate cell that can result from multiple cell fusions of uninuclear cells (i.e., cells with a single nucleus), i ...

. 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 Senescence () or biological aging is the gradual deterioration of Function (biology), functional characteristics in living organisms. Whole organism senescence involves an increase in mortality rate, death rates or a decrease in fecundity with ...

by fusion into the syncytiotrophoblast. 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. The name syncytin derives from its involvement in the formation of

, 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). This receptor places syncytin-1 in a large viral interference group called retroviral mammalian type D receptor (RDR) interference group. Syncytin-1 has been shown to interfere with viral infection ''in-vitro'' by RDR interference group member spleen necrosis virus. 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. 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. 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. 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. 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. 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. 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 Membrane proteins are common proteins that are part of, or interact with, biological membranes. Membrane proteins fall into several broad categories depending on their location. Integral membrane proteins are a permanent part of a cell membrane ...

and has a relatively long

cytoplasm The cytoplasm describes all the material within a eukaryotic or prokaryotic cell, enclosed by the cell membrane, including the organelles and excluding the nucleus in eukaryotic cells. The material inside the nucleus of a eukaryotic cell a ...

ic 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.

Clinical significance

Pre-eclampsia

Hypoxic conditions characteristic of

Pre-eclampsia Pre-eclampsia is a multi-system disorder specific to pregnancy, characterized by the new onset of hypertension, high blood pressure and often a significant amount of proteinuria, protein in the urine or by the new onset of high blood pressure a ...

and IUGR are associated with abnormal expression of syncytin-1 in

cells and pre-eclamptic placental tissue has reduced levels of syncytin-1 expression. 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. 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 Bipolar disorder (BD), previously known as manic depression, is a mental disorder characterized by periods of Depression (mood), depression and periods of abnormally elevated Mood (psychology), mood that each last from days to weeks, and in ...

and

schizophrenia Schizophrenia () is a mental disorder characterized variously by hallucinations (typically, Auditory hallucination#Schizophrenia, hearing voices), delusions, thought disorder, disorganized thinking and behavior, and Reduced affect display, f ...

. *

References

External links

ERVW-1
on the Atlas of Genetics and Oncology {{Retroviruses Endogenous retroviruses