Syncytin Genes Research Articles

Impact of Metabolic Stress on BeWo Syncytiotrophoblast Function.

During placental formation, cytotrophoblasts (CTBs) fuse into multinucleate, microvilli-coated syncytiotrophoblasts (STBs), which contact maternal blood, mediating nutrient, metabolite, and gas exchange between mother and fetus, and providing a barrier against fetal infection. Trophoblasts remodel the surrounding extracellular matrix through the secretion of matrix metalloproteinases (MMPs). Maternal obesity and diabetes mellitus can negatively impact fetal development and may impair trophoblast function. We sought to model the impact of metabolic stress on STB function by examining MMP and hormone secretion. The BeWo CTB cell line was syncytialized to STB-like cells with forskolin. Cell morphology was examined by electron microscopy and immunofluorescence; phenotype was further assessed by ELISA and RT-qPCR. STBs were exposed to a metabolic stress cocktail (MetaC: 30 mM glucose, 10 nM insulin, and 0.1 mM palmitic acid). BeWo syncytialization was demonstrated by increased secretion of HCGβ and progesterone, elevated syncytin gene expression (ERVW-1 and ERVFRD-1), loss of tight junctions, and increased surface microvilli. MetaC strongly suppressed syncytin gene expression (ERVW-1 and ERVFRD-1), suppressed HCGβ and progesterone secretion, and altered both MMP-9 and MMP-2 production. Metabolic stress modeling diabetes and obesity altered BeWo STB hormone and MMP production in vitro.

Senescent cells and cancer cells as apoptosis suppressors: Causes and effects

The death of some senescent cells (KS), as well as neoplastic cells (KN), can be paradoxically inhibited at the stage of apoptosis. Thus, the KS become inhibitors of oncogenesis at the beginning of the phenomenon. The influence of KS and KN on the inhibition of apoptosis is multidirectional, which is presented graphically in the form of Euler’s mathematical circles (Fig. 2). Senescence, like apoptosis, may to some extent inhibit oncogenesis. The neoplastic process is also associated with non-apoptotic death, i.e. entosis, as well as autophagy, i.e. autophagocytosis with the participation of lysosomes. The process of autophagy may also involve the cell proteolytic system via the ubiquitin-proteasome system (UPS), in which polyubiquitination of suppressor proteins, e.g. p53 protein, leads to oncogenesis. Therefore, both of the above-mentioned processes of autophagy favour oncogenesis. The paper also presents the role of human endogenous retroviruses (HERs) in oncogenesis, with particular emphasis on the syncytin gene and its participation in the induction of placental cancer (choriocarcinoma, chorioepithelioma).

An ancient retroviral RNA element hidden in mammalian genomes and its involvement in co-opted retroviral gene regulation

BackgroundRetroviruses utilize multiple unique RNA elements to control RNA processing and translation. However, it is unclear what functional RNA elements are present in endogenous retroviruses (ERVs). Gene co-option from ERVs sometimes entails the conservation of viral cis-elements required for gene expression, which might reveal the RNA regulation in ERVs.ResultsHere, we characterized an RNA element found in ERVs consisting of three specific sequence motifs, called SPRE. The SPRE-like elements were found in different ERV families but not in any exogenous viral sequences examined. We observed more than a thousand of copies of the SPRE-like elements in several mammalian genomes; in human and marmoset genomes, they overlapped with lineage-specific ERVs. SPRE was originally found in human syncytin-1 and syncytin-2. Indeed, several mammalian syncytin genes: mac-syncytin-3 of macaque, syncytin-Ten1 of tenrec, and syncytin-Car1 of Carnivora, contained the SPRE-like elements. A reporter assay revealed that the enhancement of gene expression by SPRE depended on the reporter genes. Mutation of SPRE impaired the wild-type syncytin-2 expression while the same mutation did not affect codon-optimized syncytin-2, suggesting that SPRE activity depends on the coding sequence.ConclusionsThese results indicate multiple independent invasions of various mammalian genomes by retroviruses harboring SPRE-like elements. Functional SPRE-like elements are found in several syncytin genes derived from these retroviruses. This element may facilitate the expression of viral genes, which were suppressed due to inefficient codon frequency or repressive elements within the coding sequences. These findings provide new insights into the long-term evolution of RNA elements and molecular mechanisms of gene expression in retroviruses.

Differential Expression Pattern of Retroviral Envelope Gene in the Equine Placenta.

Endogenous retroviruses (ERVs) are proviral phases of exogenous retroviruses, which have coevolved with vertebrate genomes for millions of years. The conservation of ERV genes throughout evolution suggests their beneficial effects on their hosts' survival. An example of such positive selection is demonstrated by the syncytin gene, which encodes a protein with affinity for various mammalian placentas that is involved in the formation of syncytiotrophoblasts. Although the horse has an epitheliochorial placenta, in which the fetal trophoblasts are simply apposed to the intact uterine epithelium, we have previously demonstrated that the equine ERV (EqERV) env RNA is unexpectedly expressed in placental tissue. In the present study, we investigated the mRNA expression pattern of the EqERV env gene in different parts of the equine placenta, to gain more insight into its putative role in the fetal–maternal relationship. To this end, we used reverse transcription–quantitative PCR (RT–qPCR) and in situ hybridization assays to analyze different target areas of the equine placenta. The retroviral env gene is expressed in the equine placenta, even though there is no syncytium or erosion of the uterine endometrium. The gene is also expressed in all the sampled areas, although with some quantitative differences. We suggest that these differences are attributable to variations in the density, height, and degree of morphological complexity of the chorionic villi forming the microcotyledons. The involvement of the EqERV env gene in different functional pathways affecting the fetus–mother relationship can be hypothesized.

ZBED6 binding motifs correlate with endogenous retroviruses and Syncytin genes.

Retroviruses have infiltrated vertebrate germlines for millions of years as inherited endogenous retroviruses (ERVs). Mammalian genomes host large numbers of ERVs and transposable elements (TEs), including retrotransposons and DNA transposons, that contribute to genomic innovation and evolution as coopted genes and regulators of diverse functions. To explore features distinguishing coopted ERVs and TEs from other integrations, we focus on the potential role of ZBED6 and repeated ERV domestication as repurposed Syncytin genes. The placental mammal-specific ZBED6 is a DNA transposon-derived transcription regulator and we demonstrate that its binding motifs are associated with distinct Syncytins and that ZBED6 binding motifs are 2- to 3-fold more frequent in ERVs than in flanking DNA. Our observations suggest that ZBED6 could contribute an extended regulatory role of genomic expression, utilizing ERVs as platforms for genomic innovation and evolution.

Molecular Mechanisms of Trophoblast Dysfunction Mediated by Imbalance between STOX1 Isoforms.

SummarySTOX1 is a transcription factor involved in preeclampsia and Alzheimer disease. We show that the knock-down of the gene induces rather mild effect on gene expression in trophoblast cell lines (BeWo). We identified binding sites of STOX1 shared by the two major isoforms, STOX1A and STOX1B. Profiling gene expression of cells overexpressing either STOX1A or STOX1B, we identified genes downregulated by both isoforms, with a STOX1 binding site in their promoters. Among those, STOX1-induced Annexin A1 downregulation led to abolished membrane repair in BeWo cells. By contrast, overexpression of STOX1A or B has opposite effects on trophoblast fusion (acceleration and inhibition, respectively) accompanied by syncytin genes deregulation. Also, STOX1A overexpression led to abnormal regulation of oxidative and nitrosative stress. In sum, our work shows that STOX1 isoform imbalance is a cause of gene expression deregulation in the trophoblast, possibly leading to placental dysfunction and preeclampsia.

Expression of the syncytin-1 and syncytin-2 genes in the trophoblastic tissue of the early pregnancy losses with normal and abnormal karyotypes.

Syncytin-1 and syncytin-2 which are endogenous retroviral genes products play a great role in syncytialization during trophoblast differentiation in normal placental tissues. In aneuploidic placentas due to the low level of pregnancy-induced hormones an alteration was occurred in the syncytialization process, while in the presence of cytogenetically abnormal karyotype the effect of syncytin gene expression levels on syncytialization process and in occured to spontaneous abortions is not clear. To reveal this, we investigated in syncytin-1 and syncytin-2 genes expression levels of chromosomally abnormal and normal trophophoblastic tissues and we also discussed the effect of the syncytin gene expression levels to the occurense of the spontaneous abortion. To each one of the trophoblastic cells; cultivation, harvesting, banding, and analysis were performed and the chromosomes were classified according to the presence of abnormality and normal XY constitution. To exclude the maternal decidual cell contamination, female karyotyped abortion materials were omitted in control group. The patient group consisted of thirty six placental tissues including trisomy 16 (n=10), triploidy (n=9), monosomyX(n=9), trisomy 21 (n=5) and trisomy 7 (n=3). The control group was consisting twenty placental tissues with XY karyotypes. The some part of the dissected frozen trophoblastic cells were used for RNA isolation and were proceeded to the determination of the expression levels of syncytin-1 and syncytin-2 genes by single-step Real Time PCR. The cDNAs were obtained by probes used in the same PCR stages. The sequence analysis of the syncytin-1 and syncytin-2 genes were performed, and read by the usage of the FinchTV 1.4.0 program. Between the expression levels of syncytin-1 and syncytin-2 genes were statistically difference in the patients and controls. There was a difference (p<0.0001) between trisomy 7 and other patient groups and controls, regarding to the expression of syncytin-1 gene. Numerous mutations in the syncytin-1 and syncytin-2 genes (on the expression sites) were detected, and the mutation rate was higher in the syncytin-1 gene compared to the syncytin-2 gene in the patient and in the control groups (p<0.001). The results of the study indicate that the expression of the syncytin-2 genes could be altered in the presence of chromosomally abnormal trophoblastic tissues, and these could lead to the loss of pregnancy due to the insufficient syncytialization. In sum, the current research has value for the further studies covering the mechanisms of trophoblast cell fusion, and syncytiotrophoblast regeneration, and thus the pathophysiology of human placental development in the presence of genomic anomaly.

Novel Molecular Mechanisms of Trophoblast Dysfunction Mediated by Imbalance between STOX1 Isoforms

STOX1 is a transcription factor involved in two complex and frequent human diseases, preeclampsia and Alzheimer disease. However, precisely how STOX1 controls gene expression is still not well known. In this study, we identified binding sites of STOX1shared by the two major isoforms of the protein, STOX1A and STOX1B. Using newly generated villous trophoblast cell lines overexpressing either STOX1A or STOX1B, we identified a group of genes down-regulated by both isoforms, which contains one of the STOX1 binding sites that we identified in their promoters. Amongst those gene Annexin A1 (a major protein for membrane repair) was drastically down-regulated. We show that membrane repair was consistently abolished in BeWo cells overexpressing STOX1 isoforms. We then studied the effect of STOX on trophoblast fusion, a major event in villous trophoblast biology. STOX1A and B overexpression had opposite effects on trophoblast fusion: STOX1A accelerated the process and STOX1B prevented it in particular by deregulating syncytin genes which are endoretroviruses crucial for trophoblast fusion in mammals and other viviparous vertebrates. We also show that STOX1A overexpression led to abnormal regulation of oxidative and nitrosative stress in the cells. In sum STOX1 isoform imbalance appears as a possible cause of deregulation of gene expression in trophoblast, possibly leading to placental dysfunction and preeclampsia.

The evolution of endogenous retroviral envelope genes in bats and their potential contribution to host biology

Bats are the primary reservoirs and carriers of a wide range of viruses of unknown infectivity and pathogenic potential. Some of those if transmitted to other species can cause enormous economic losses in agriculture, and mortality in humans. Bats can be persistently infected with viruses while not showing any symptoms of disease, despite having high virus titre levels in their tissues and shedding virions for months or years after primary infection. It has been suggested that the lack of symptoms of viral infections and low mortality rate in bats might be due to immune adaptations that result from their long-term co-evolution with viruses. In this study, we screened all publicly available bat genomes from six bat families within which we have identified several envelope sequences of retroviral origin (gammaretroviruses). We analysed the identified sequences with Bayesian methods and maximum-likelihood inference to generate a phylogenetic tree with additional reference sequences of known endogenous and exogenous viral envelope genes. We also identified groups of orthologous viral envelopes and analysed them to determine if any of them might be an EVE (endogenous virus element) with an EDI (EVE- derived immunity) function or a candidate for a bat syncytin gene, which is an endogenized viral envelope, mostly known from its function in placentation in animals. Our study shows that bat genomes contain a substantial number of large, intact envelopes with open reading frames, which were found clustering closely on a phylogenetic tree reconstruction with syncytin sequences of other species. That might indicate that such sequences are good candidates for further bat-syncytin/EDI search.

An endogenous retroviral envelope syncytin and its cognate receptor identified in the viviparous placental Mabuya lizard

Syncytins are envelope genes from endogenous retroviruses that have been captured during evolution for a function in placentation. They have been found in all placental mammals in which they have been searched, including marsupials. Placental structures are not restricted to mammals but also emerged in some other vertebrates, most frequently in lizards, such as the viviparous Mabuya Scincidae. Here, we performed high-throughput RNA sequencing of a Mabuya placenta transcriptome and screened for the presence of retroviral env genes with a full-length ORF. We identified one such gene, which we named "syncytin-Mab1," that has all the characteristics expected for a syncytin gene. It encodes a membrane-bound envelope protein with fusogenic activity ex vivo, is expressed at the placental level as revealed by in situ hybridization and immunohistochemistry, and is conserved in all Mabuya species tested, spanning over 25 My of evolution. Its cognate receptor, required for its fusogenic activity, was searched for by a screening assay using the GeneBridge4 human/Chinese hamster radiation hybrid panel and found to be the MPZL1 gene, previously identified in mammals as a signal-transducing transmembrane protein involved in cell migration. Together, these results show that syncytin capture is not restricted to placental mammals, but can also take place in the rare nonmammalian vertebrates in which a viviparous placentotrophic mode of reproduction emerged. It suggests that similar molecular tools have been used for the convergent evolution of placentation in independently evolved and highly distant vertebrates.

Genetic Evidence That Captured Retroviral Envelope syncytins Contribute to Myoblast Fusion and Muscle Sexual Dimorphism in Mice.

Syncytins are envelope genes from endogenous retroviruses, “captured” for a role in placentation. They mediate cell-cell fusion, resulting in the formation of a syncytium (the syncytiotrophoblast) at the fetomaternal interface. These genes have been found in all placental mammals in which they have been searched for. Cell-cell fusion is also pivotal for muscle fiber formation and repair, where the myotubes are formed from the fusion of mononucleated myoblasts into large multinucleated structures. Here we show, taking advantage of mice knocked out for syncytins, that these captured genes contribute to myoblast fusion, with a >20% reduction in muscle mass, mean muscle fiber area and number of nuclei per fiber in knocked out mice for one of the two murine syncytin genes. Remarkably, this reduction is only observed in males, which subsequently show muscle quantitative traits more similar to those of females. In addition, we show that syncytins also contribute to muscle repair after cardiotoxin-induced injury, with again a male-specific effect on the rate and extent of regeneration. Finally, ex vivo experiments carried out on murine myoblasts demonstrate the direct involvement of syncytins in fusion, with a >40% reduction in fusion index upon addition of siRNA against both syncytins. Importantly, similar effects are observed with primary myoblasts from sheep, dog and human, with a 20–40% reduction upon addition of siRNA against the corresponding syncytins. Altogether, these results show a direct contribution of the fusogenic syncytins to myogenesis, with a demonstrated male-dependence of the effect in mice, suggesting that these captured genes could be responsible for the muscle sexual dimorphism observed in placental mammals.

Baton pass hypothesis: successive incorporation of unconserved endogenous retroviral genes for placentation during mammalian evolution.

It is well accepted that numerous RNAs derived from endogenous retroviruses (ERVs) are expressed in mammalian reproductive structures, particularly in the uterus, trophoblast, and placenta. Syncytin 1 and syncytin 2 in humans and syncytin A and syncytin B in mice are membrane proteins originating from Env genes of ERVs. These ERVs are involved in the fusion of trophoblast cells, resulting in multinucleated syncytiotrophoblast formation. Evidence accumulated indicates that syncytin-like fusogenic proteins are expressed in the placenta of rabbits, dogs/cats, ruminant ungulates, tenrecs, and opossums. The syncytin genes so far characterized are known to be endogenized to the host genome only within the past 12-80 million years, more recently than the appearance of mammalian placentas, estimated to be 160-180 million years ago. We speculate that ERVs including syncytin-like gene variants integrated into mammalian genomes in a locus-specific manner have replaced the genes previously responsible for cell fusion. We therefore propose the 'baton pass' hypothesis, in which multiple successive ERV variants 'take over' cell-fusion roles, resulting in increased trophoblast cell fusion, morphological variations in placental structures, and enhanced reproductive success in placental mammals.

Promoter Hypermethylation and Decreased Expression of Syncytin-1 in Pancreatic Adenocarcinomas.

Syncytin-1 is a member of human endogenous retroviral W gene family (HERVW1). Known to be expressed in human placental trophoblast, syncytin-1 protein mediates the fusion of cytotrophoblasts for the formation of syncytiotrophoblasts, the terminally differentiated form of trophoblast lineage. In addition, in vitro studies indicate that syncytin-1 possessed nonfusogenic functions such as those for immune suppression, cell cycle regulation and anti-apoptotic activities. Overexpression of syncytin-1 has been observed in various malignant tissues including breast, endometrial and ovarian cancers. It was reported that syncytin-1 gene expression is associated with dynamic changes of DNA hypomethylation in the 5’ LTR. In this study, applying the real-time PCR, Western blot analysis and immunohistochemistry methods, we demonstrate a constitutive expression of syncytin-1 in normal pancreas tissues as well as normal tissues adjacent to cancer lesions. Moreover, a reduced expression is found in the pancreatic adenocarcinoma tissues. The expression levels of syncytin-1 are not correlated with the stage, historical grade and gender, but inversely correlated with patients’ age. Furthermore, COBRA and bisulfite sequencing results indicated that the lower expression of syncytin-1 is correlated with the hypermethylation of two CpG dinucleotides in the 5’ LTR of syncytin-1 gene. The nonfusogenic function of syncytin-1 in normal pancreas as well as its role(s) in the pathogenesis and progression of pancreatic cancers remains to be investigated. Identification of the two CpG dinucleotides around transcription start site as key epigenetic elements has provided valuable information for further studies on the epigenetic regulation of syncytin-1 in pancreatic cancer cells.

Retroviral envelope gene captures and syncytin exaptation for placentation in marsupials

Syncytins are genes of retroviral origin captured by eutherian mammals, with a role in placentation. Here we show that some marsupials-which are the closest living relatives to eutherian mammals, although they diverged from the latter ∼190 Mya-also possess a syncytin gene. The gene identified in the South American marsupial opossum and dubbed syncytin-Opo1 has all of the characteristic features of a bona fide syncytin gene: It is fusogenic in an ex vivo cell-cell fusion assay; it is specifically expressed in the short-lived placenta at the level of the syncytial feto-maternal interface; and it is conserved in a functional state in a series of Monodelphis species. We further identify a nonfusogenic retroviral envelope gene that has been conserved for >80 My of evolution among all marsupials (including the opossum and the Australian tammar wallaby), with evidence for purifying selection and conservation of a canonical immunosuppressive domain, but with only limited expression in the placenta. This unusual captured gene, together with a third class of envelope genes from recently endogenized retroviruses-displaying strong expression in the uterine glands where retroviral particles can be detected-plausibly correspond to the different evolutionary statuses of a captured retroviral envelope gene, with only syncytin-Opo1 being the present-day bona fide syncytin active in the opossum and related species. This study would accordingly recapitulate the natural history of syncytin exaptation and evolution in a single species, and definitely extends the presence of such genes to all major placental mammalian clades.

The captured retroviral envelope syncytin-A and syncytin-B genes are conserved in the Spalacidae together with hemotrichorial placentation.

Syncytins are fusogenic envelope (env) genes of retroviral origin that have been captured for a function in placentation. Multiple independent events of syncytin gene capture were found to have occurred in primates, rodents, lagomorphs, carnivores, and ruminants. In the mouse, two syncytin-A and -B genes are present, which trigger the formation of the two-layered placental syncytiotrophoblast at the maternal-fetal interface, a structure classified as hemotrichorial. Here, we identified syncytin-A and -B orthologous genes in the genome of all Muroidea species analyzed, thus dating their capture back to about at least 40 million years ago, with evidence that they evolved under strong purifying selection. We further show, in the divergent Spalacidae lineage (blind mole rats [Spalax]), that both syncytins have conserved placenta-specific expression, as revealed by RT-PCR analysis of a panel of Spalax galili tissues, and display fusogenic activity, using ex vivo cell-cell fusion assays. Refined analysis of the placental architecture and ultrastructure revealed that the Spalax placenta displays a hemotrichorial organization of the interhemal membranes, as similarly observed for other Muroidea species, yet with only one trophoblastic cell layer being clearly syncytialized. In situ hybridization experiments further localized syncytin transcripts at the level of these differentiated interhemal membranes. These findings argue for a role of syncytin gene capture in the establishment of the original hemotrichorial placenta of Muroidea, and more generally in the diversity of placental structures among mammals.

Independent captures of syncytin genes in the three clades of the order Rodentia in relation with placental diversity

Independent captures of syncytin genes in the three clades of the order Rodentia in relation with placental diversity

Hypomethylation and Activation of Syncytin-1 Gene in Endometriotic Tissue

Syncytin-1 plays a critical role in the maintenance of normal pregnancy by mediating the formation of syncytiotrophoblasts through a fosugenic action. Encoded by the human endogenous retrovirus envelope gene HERV-W, syncytin-1 trophoblast-specific expression is controlled by epigenetic mechanisms. In non-placental tissues, the syncytin-1 gene is suppressed by hypermethylation in the LTR promoter region. Hypomethylated and activated syncytin-1 gene is found in placental trophoblast lineages and malignant cells. We here demonstrate that while syncytin-1 gene remains silenced in the eutopic endometrium from endometriotic patients, syncytin-1 mRNA and protein are detected in ectopic, endometriotic lesions; particularly the endometrioid glandular endothelial cells. LINE-1 COBRA assay and immunohistochemistry using the 5-MC-specific antibody did not detect any changes in global DNA methylation in the endometriotic tissues. However, results from COBRA and bisulfite sequencing indicated that the LTR region of the syncytin-1 promoter is hypomethylated in endometriotic tissues, highlighting the significance of DNA demethylation in syncytin-1 gene activation. Analysis of DNA methyltransferase 3B (DNMT3B) mRNA levels revealed that DNMT3B3, an isoform carrying methyltransferase activity, is downregulated; whereas DNMT3B7, the isoform without enzymatic activity, is upregulated in the endometriotic tissues, pointing to positive and negative regulatory functions, respectively, of these isoforms on syncytin-1 methylation. These results have provided the first evidence supporting the involvement of epigenetic mechanisms for syncytin-1 upregulation in endometriotic tissues. Considering recent findings on the nonfusogenic activity of syncytin-1, its expression in endometriotic tissues suggests that this multifunctional protein may be implicated in the pathogenesis and/or progression of endometriosis.

Decreased Expression and Altered Methylation of Syncytin-1 Gene in Human Placentas Associated with Preeclampsia

Syncytin-1 is a protein coded by a human endogenous retrovirus (HERV) gene of the HERV-W family (HERVWE1). Syncytin- 1 mediates formation of syncytiotrophoblasts through fusion of cytotrophoblasts, a hallmark of terminal differentiation of placental trophoblast linage. Syncytin-1 also possesses nonfusogenic functions and regulates cell cycle progression. While decreased syncytin-1 expression and syncytium deficiency are considered important pathological changes in preeclampsia, the molecular mechanism(s) underlying syncytin-1 downregulation remains unclear. In this study, we confirmed that expression levels of syncytin-1 mRNA and protein were significantly lower in preeclamptic placentas compared to normal controls. Human chorionic somatomammotropin expression, a marker for syncytium function, was also decreased in preeclamptic placentas. The mRNA levels of ASCT2, the syncytin-1 receptor involved in cell fusion process, and GCMa, a transcriptional factor known to regulate syncytin-1 expression, were not significantly altered. Methylation in the 5'LTR of syncytin-1 promoter was quantified by COBRA, methylation-specific PCR, and DNA sequencing. Results from all three assays indicated significantly hypermethylated syncytin-1 promoter in preeclamptic placentas compared to normal controls. Methylation levels were inversely correlated with syncytin-1 mRNA levels, suggesting that hypermethylation may lead to syncytin-1 downregulation. Further experiments indicated that DNMT1 and DNMT3B3 mRNA and protein levels were increased in preeclamptic placentas, suggesting that higher DNA methyltransferase activity may contribute to the hypermethylation of syncytin-1 in preeclamptic placentas. These results indicated that aberrant hypermethylation is involved in downregulation of syncytin-1, and epigenetic alterations may play a significant role in the development of preeclampsia.

Y.W. Loke, Life's Vital Link: The Astonishing Role of the Placenta

Y.W. Loke, Life's Vital Link: The Astonishing Role of the Placenta

Immunosuppressive domains of retroviruses: Cell mechanisms of the effect on the human immune system

Immunosuppressive domains (ISDs) of viral envelope glycoproteins provide highly pathogenic phenotypes to various retroviruses. The ISD interaction with immune cells leads to an inhibition of the response. As was shown in the 1980s, a 17-amino acid residue of ISD fragment (known as CKS-17) is responsible for this immune modulation. However, the underlying mechanisms were unknown. Thorough research identified activation of signal transduction via the Ras-Raf-MEK-MAPK and PI3K-AKT-mTOR cell pathways as a result of the ISD interaction with immune cells. The result is the decrease in the secretion of stimulatory cytokines (e.g., IL-12) and increase of inhibitory and anti-inflammatory cytokines (e.g., IL-10). One of the receptor tyrosine kinases that triggers signal transduction in these pathways acts as a primary ISD target, while other key regulators, cAMP and diacylglycerol (DAG), act as secondary messengers. Immunosuppressive-like domains are not restricted to retroviruses; an ISD present in Ebola virus envelope glycoproteins determines an extremely severe clinical course of virus-induced hemorrhagic fever. A number of retrovirus-originating ISD-coding regions are found in the human genome. The regions are expressed as parts of the syncytin genes in the placenta, helping to render the mother’s immune system tolerant of the placenta and embryo. The review considers the molecular aspects of the retroviral ISD-induced modulation of the host immune system.