Syncytin

Structure

Syncytin is a human endogenous envelope protein and is found in the human placenta. There are two forms of syncytin; syncytin 1 and , and they are both critical for fetal implantation and placental development. Syncytin 1 contains 538 amino acids and is located on the human chromosome 7 while the specific HERV-W1 coding region is located at 7q21.2. Syncytin has two domains, the surface unit and the transmembrane unit. The surface unit of syncytin 1 is what binds to receptors on the host cell whereas the transmembrane unit supports the fusion of two cells ^[1]. The structure of syncytin is composed of three identical monomers and the precursor that synthesizes the formation is glycosylated gPr73. Once the precursor is cleaved at the surface unit and the transmembrane unit, both units covalently bond via . The transmembrane unit is significant as it contains immunosuppressive domain known as the fusion peptide that plays a critical role in the tolerance a mother has to her fetus during pregnancy ^[2]. Thus, the mother’s immune system does not “attack” the fetus as if it is a foreign body.

Function

Syncytin-1 and Syncytin-2 are both fusogenic which means they facilitate the fusion of cells. Together, the proteins are required for the proper placental formation and maintenance ^[2]. The of the membrane occurs after conformational changes occur within the surface unit and the transmembrane unit. For these changes to occur, the surface unit has to bind with specific cells to release the “cap” which then opens up the space of the transmembrane unit to be exposed. This then creates a hairpin that then allows for the fusion of the two membranes together as it brings them close enough for the interaction to occur. In order for this to occur, the fusion of cells together creates syncytiotrophoblasts and these structures allow for the exchange of maternal blood with fetal blood and ultimately establish the flow of nutrients, oxygen transport, and hormone synthesis as well ^[3]. This allows for the fetus to grow and develop. However, when unregulated or in excess, Syncytin-1 has been linked to several diseases. The increased inflammatory response has been linked to individuals with a higher level of Syncytin-1 which has been shown to increase the likeliness of developing neuropsychological disorders ^[1].

Evolutionary Relevance

8% of the human genome consists of human endogenous retroviruses and these human endogenous retroviruses have been linked to the early evolution of primates due to germline infections of exogenous retroviruses. These retroviruses consist of the genes gag, pro, pol, and env. The env gene is associated with the envelope of the retrovirus and has been linked to prompting cancerogenesis and the gag and pol genes have been linked to the inactivation of mutations. Syncytin-1 has been found to have been conserved throughout hominoids and has maintained fusogenic activity. The gene itself has become a key factor for reproduction in mammals. This implies that Syncytin-1 has been co-opted by hominoids for placental development as well and the proper blood barrier needed to supply the fetus with nutrients and other materials needed for the growth and development of the fetus. The immunosuppression of the mother’s immune system plays a critical role in the survival of the fetus and its development. This increases the viability of pregnancy and decreases the chance of pregnancy loss which is beneficial to mammalian species ^[4].

Disease

Multiple Sclerosis (MS)

An increase in the expression of Syncytin-1 has been directly correlated to the development of multiple sclerosis. It was also found that syncytin-1 could induce inflammation and was found to cause neurotoxic cascades as well. This neurotoxic cascade includes the secretion of proinflammatory cytokines. Multiple sclerosis is an inflammatory disorder that causes the demyelination of axons. It was found that overexpression of Syncytin-1 can cause tissue damage and demyelination if affecting glial cells. Overexpression of Syncytin-1 in immune cells that are activated in multiple sclerosis and patients that are affected with acute infections have an elevated level of monocytes that contain the protein. Along with this, after interaction with lipopolysaccharides, the level of syncytin-1 also increased in T and B lymphocytes along with natural killer cells which implies that syncytin-1 may have a role in immune cell activation in the early stages and may even be involved in the pathogenesis of multiple sclerosis ^[1].

Schizophrenia

The overexpression of Syncytin-1 has also been loosely correlated to disorders such as schizophrenia. Brain-derived neurotrophic factors, neurotrophic tyrosine kinase receptor types, and dopamine receptor D3 are all significant in the development of schizophrenia, and it was found that the overexpression of the protein in human U251 glioma cells correlates to the increase of these receptors ^[2]. Studies have shown that an increase in the transcription of syncytin-1 is also correlated to the development of schizophrenia. However, several studies have also shown that there is no significant difference in the expression level of syncytin-1 in the development of schizophrenia ^[1]. However, these findings imply that syncytin may have a variety of different ways of affecting the development of schizophrenia.

Alzheimer's Disease

An abnormal influx of calcium has been linked to the development of Alzheimer’s Disease in individuals. Overexpression of syncytin-1 has been linked to the influx of calcium ions in neuroblastoma cells. Along with the influx of calcium, nitric oxide also contributes to the development of Alzheimer’s Disease as it regulates the inflammatory response of the brain and neuronal cells ^[2]. An increase in syncytin-1 levels has the capability to activate the enzyme Nitric Oxide Synthase in astrocytes which then induces the release of the redox reaction product, nitric oxide. These, in turn, are cytotoxic to oligodendrocytes which can damage axons ^[1].

Cancer

Syncytin-1 has been correlated to several different kinds of cancers including breast cancer, carcinomas, and endometrial cancers. As mentioned above, the env gene of syncytin-1 can become activated and promote the production of cancerous cells ^[2]. Overexpression in syncytin-1 contributes to increased proliferation, metastasis, and the growth of tumors in individuals due to the methylation of DNA and the 5’LTR of the syncytin gene. The overmethylation contributes to the silencing of the tumor-suppressing gene ^[5]. As a result, if both tumor suppressor genes in a cell contain a mutation, then the suppressor gene is deactivated. With the tumor suppressor gene losing function, cells may grow and divide unregulated, resulting in cancer.

Syncytiin 3D structures

5ha6, 6rx1 – hSct1 fusion subunit 343-435 – human
1y4m, 6rx3 – hSct2 fusion subunit 375-468
7oix – hSct2 + MFSD2A – Cryo EM