RESUMEN
OBJECTIVES: Human endogenous retroviruses (HERVs) are integral components of the human genome, and their reactivation has been implicated in the pathogenesis of some malignancies. External viral co-infections are suspected to play a role in HERV transactivation. This study aimed to investigate the expression of HERV-K np9 elements and HERV-R env gene in pediatric acute lymphoblastic leukemia (ALL) patients. Additionally, we explored potential correlations between HERV expression and common viral infections prevalent in this group of patients. METHODS: Blood samples were collected from 43 pediatric ALL patients and 48 age- and sex-matched healthy controls. Quantitative real-time PCR (qRT-PCR) was used to assess the expression of HERV-K np9 and HERV-R env, along with herpes simplex virus (HSV), parvovirus B19, and polyomavirus BK. RESULTS: HERV-K np9 and HERV-R env showed significantly higher expression in the peripheral blood of ALL patients compared to healthy controls (p < .001 and p = .003, respectively). HSV positivity was associated with significantly increased HERV-K np9 expression. No significant correlations were observed between other investigated viruses and HERV gene expression. CONCLUSION: The overexpression of HERV-K np9 and HERV-R env in pediatric ALL patients suggest their potential role in leukemogenesis. Our findings also suggest a possible link between HSV infection and HERV reactivation in this population. Future investigations are needed to understand the precise roles of these genes and viral infections in the development of ALL.
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Retrovirus Endógenos , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Retrovirus Endógenos/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/virología , Masculino , Femenino , Niño , Preescolar , Productos del Gen env/genética , Productos del Gen env/metabolismo , Adolescente , Estudios de Casos y ControlesRESUMEN
The Bovine Leukemia Virus (BLV) Envelope (Env) glycoprotein complex is instrumental in viral infectivity and shapes the host's immune response. This study presents the production and characterization of a soluble furin-mutated BLV Env ectodomain (sBLV-EnvFm) expressed in a stable S2 insect cell line. We purified a 63 kDa soluble protein, corresponding to the monomeric sBLV-EnvFm, which predominantly presented oligomannose and paucimannose N-glycans, with a high content of core fucose structures. Our results demonstrate that our recombinant protein can be recognized from specific antibodies in BLV infected cattle, suggesting its potential as a powerful diagnostic tool. Moreover, the robust humoral immune response it elicited in mice shows its potential contribution to the development of subunit-based vaccines against BLV.
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Anticuerpos Antivirales , Virus de la Leucemia Bovina , Proteínas Recombinantes , Proteínas del Envoltorio Viral , Animales , Virus de la Leucemia Bovina/genética , Virus de la Leucemia Bovina/inmunología , Bovinos , Proteínas Recombinantes/genética , Ratones , Proteínas del Envoltorio Viral/genética , Proteínas del Envoltorio Viral/inmunología , Proteínas del Envoltorio Viral/metabolismo , Anticuerpos Antivirales/inmunología , Leucosis Bovina Enzoótica/virología , Línea Celular , Productos del Gen env/genética , Productos del Gen env/metabolismo , Productos del Gen env/inmunologíaRESUMEN
Endogenous retroviruses (ERVs) are remnants of ancestral viruses in the host genome. The present study identified the expression of a defective retroviral env gene belonging to the ERV group V member Env (EnvV) in Felis catus (EnvV-Fca). EnV-Fca was specifically detected in the placental trophoblast syncytiotrophobic layer and expressed as a secreted protein in cultured cells. Genetic analyses indicated that EnvV2 genes are widely present in vertebrates and are under purifying selection among carnivores, suggesting a potential benefit for the host. This study suggests that birds, bats, and rodents carrying EnvV2 may play significant roles as intermediate vectors in spreading or cross-transmitting viruses among species. Our findings provide valuable insights into the evolution of ERV in vertebrate hosts.
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Retrovirus Endógenos , Productos del Gen env , Placenta , Animales , Gatos , Retrovirus Endógenos/genética , Femenino , Embarazo , Productos del Gen env/genética , Productos del Gen env/metabolismo , Placenta/virología , Placenta/metabolismo , Filogenia , Secuencia de Aminoácidos , Humanos , Trofoblastos/metabolismo , Trofoblastos/virologíaRESUMEN
Endogenous retroviruses (ERVs) are remnants of ancestral viral infections. Feline leukemia virus (FeLV) is an exogenous and endogenous retrovirus in domestic cats. It is classified into several subgroups (A, B, C, D, E, and T) based on viral receptor interference properties or receptor usage. ERV-derived molecules benefit animals, conferring resistance to infectious diseases. However, the soluble protein encoded by the defective envelope (env) gene of endogenous FeLV (enFeLV) functions as a co-factor in FeLV subgroup T infections. Therefore, whether the gene emerged to facilitate viral infection is unclear. Based on the properties of ERV-derived molecules, we hypothesized that the defective env genes possess antiviral activity that would be advantageous to the host because FeLV subgroup B (FeLV-B), a recombinant virus derived from enFeLV env, is restricted to viral transmission among domestic cats. When soluble truncated Env proteins from enFeLV were tested for their inhibitory effects against enFeLV and FeLV-B, they inhibited viral infection. Notably, this antiviral machinery was extended to infection with the Gibbon ape leukemia virus, Koala retrovirus A, and Hervey pteropid gammaretrovirus. Although these viruses used feline phosphate transporter 1 (fePit1) and phosphate transporter 2 as receptors, the inhibitory mechanism involved competitive receptor binding in a fePit1-dependent manner. The shift in receptor usage might have occurred to avoid the inhibitory effect. Overall, these findings highlight the possible emergence of soluble truncated Env proteins from enFeLV as a restriction factor against retroviral infection and will help in developing host immunity and antiviral defense by controlling retroviral spread.IMPORTANCERetroviruses are unique in using reverse transcriptase to convert RNA genomes into DNA, infecting germ cells, and transmitting to offspring. Numerous ancient retroviral sequences are known as endogenous retroviruses (ERVs). The soluble Env protein derived from ERVs functions as a co-factor that assists in FeLV-T infection. However, herein, we show that the soluble Env protein exhibits antiviral activity and provides resistance to mammalian retrovirus infection through competitive receptor binding. In particular, this finding may explain why FeLV-B transmission is not observed among domestic cats. ERV-derived molecules can benefit animals in an evolutionary arms race, highlighting the double-edged-sword nature of ERVs.
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Productos del Gen env , Virus de la Leucemia Felina , Leucemia Felina , Animales , Gatos , Retrovirus Endógenos/genética , Retrovirus Endógenos/metabolismo , Productos del Gen env/genética , Productos del Gen env/metabolismo , Virus de la Leucemia Felina/clasificación , Virus de la Leucemia Felina/genética , Virus de la Leucemia Felina/metabolismo , Virus de la Leucemia del Gibón/genética , Virus de la Leucemia del Gibón/metabolismo , Leucemia Felina/genética , Leucemia Felina/metabolismo , Leucemia Felina/virología , Proteínas de Transporte de Fosfato/genética , Proteínas de Transporte de Fosfato/metabolismo , Receptores Virales/metabolismo , Infecciones por Retroviridae/metabolismo , Infecciones por Retroviridae/virología , Solubilidad , FemeninoRESUMEN
PURPOSE: Human endogenous retroviruses (HERVs) are ubiquitous genomic sequences. Normally dormant HERVs, undergo reactivation by environmental factors. This deregulation of HERVs' transcriptional equilibrium correlates with medical conditions such as multiple sclerosis (MS). Here we sought to explore whether exposing the U-87 MG astrocytoma cells to traumatic injury deregulates the expression of HERV-W family member ERVW-1 encoding syncytin-1. We also examined the expression of FURIN gene that is crucial in syncytin-1 synthesis. MATERIAL AND METHODS: Scratch assay was used as a model of cells injury in U-87 MG cells. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR), western blot (WB) and migration assay using Boyden chamber were used. Phorbol 12-myristate 13-acetate (PMA) and small interfering RNA (siRNA) were used for cell stimulation and gene expression inhibition, respectively. RESULTS: Results revealed reduced ERVW-1 expression in cells exposed to injury (p â< â0.05) while GFAP gene - a marker of active astrocytes, was upregulated (p â< â0.01). These findings were confirmed by both WB and RT-qPCR. Expression of FURIN gene was not altered after injury, but cell stimulation by PMA strongly increased FURIN expression, simultaneously downregulating ERVW-1 (p â< â0.01). SiRNA-mediated expression inhibition of ERVW-1 and FURIN influenced the mRNA level for SLC1A5 (ASCT2) - primary syncytin-1 receptor, that was significantly lower. FURIN inhibition by siRNA caused strong upregulation of ERVW-1 expression (p â< â0.01). CONCLUSION: Results showed that mechanical impact affects the expression of endogenous retroviruses in U-87 MG astrocytoma cells by scratch assay. Regulation of FURIN, a crucial enzyme in ERVW-1 turnover may support the therapy of some neurological conditions.
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Astrocitoma , Retrovirus Endógenos , Furina , ARN Interferente Pequeño , Acetato de Tetradecanoilforbol , Humanos , Furina/metabolismo , Furina/genética , Retrovirus Endógenos/genética , Astrocitoma/genética , Astrocitoma/metabolismo , Astrocitoma/patología , Astrocitoma/virología , Acetato de Tetradecanoilforbol/farmacología , ARN Interferente Pequeño/metabolismo , ARN Interferente Pequeño/genética , Silenciador del Gen , Cicatrización de Heridas/efectos de los fármacos , Productos del Gen env/metabolismo , Productos del Gen env/genética , Línea Celular Tumoral , Proteínas Gestacionales/genética , Proteínas Gestacionales/metabolismo , Regulación Neoplásica de la Expresión Génica , Movimiento CelularRESUMEN
The HIV-1 Envelope (Env) protein cytoplasmic tail (CT) recently has been shown to assemble an unusual trimeric baseplate structure that locates beneath Env ectodomain trimers. Mutations at linchpin residues that help organize the baseplate impair virus replication in restrictive T cell lines but not in permissive cell lines. We have identified and characterized a second site suppressor of these baseplate mutations, located at residue 34 in the viral matrix (MA) protein, that rescues viral replication in restrictive cells. The suppressor mutation was dependent on the CT to exert its activity and did not appear to affect Env protein traffic or fusion functions in restrictive cells. Instead, the suppressor mutation increased Env incorporation into virions 3-fold and virus infectivity in single-round infections 10-fold. We also found that a previously described suppressor of Env-incorporation defects that stabilizes the formation of MA trimers was ineffective at rescuing Env baseplate mutations. Our results support an interpretation in which changes at MA residue 34 induce conformational changes that stabilize MA lattice trimer-trimer interactions and/or direct MA-CT associations.IMPORTANCEHow HIV-1 Env trimers assemble into virus particles remains incompletely understood. In restrictive cells, viral incorporation of Env is dependent on the Env CT and on the MA protein, which assembles lattices composed of hexamers of trimers in immature and mature viruses. Recent evidence indicates that CT assembles trimeric baseplate structures that require membrane-proximal residues to interface with trimeric transmembrane domains and C-terminal helices in the CT. We found that mutations of these membrane-proximal residues impaired replication in restrictive cells. This defect was countered by a MA mutation that does not localize to any obvious interprotein regions but was only inefficiently suppressed by a MA mutation that stabilizes MA trimers and has been shown to suppress other CT-dependent Env defects. Our results suggest that efficient suppression of baseplate mutations involves stabilization of MA inter-trimer contacts and/or direct MA-CT associations. These observations shed new light on how Env assembles into virions.
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Productos del Gen env , VIH-1 , Productos del Gen env del Virus de la Inmunodeficiencia Humana , Antígenos Virales/genética , Línea Celular , Productos del Gen env/química , Productos del Gen env/genética , VIH-1/fisiología , Mutación , Dominios Proteicos , Proteínas de la Matriz Viral/metabolismo , Replicación Viral/genética , Productos del Gen env del Virus de la Inmunodeficiencia Humana/química , Productos del Gen env del Virus de la Inmunodeficiencia Humana/genéticaRESUMEN
The role of retroviral envelope proteins belonging to the Human Endogenous Retroviral family 'W' (HERV-W), specifically syncytin-1 and pathogenic HERV-W (pHERV-W), as potential risk factors in multiple sclerosis (MS) has been established. This study aimed to investigate the humoral response to syncytin-1 and pHERV-W-derived peptides in a group of relapsing remitting MS patients categorized as having acute or stable disease. Furthermore, an inhibition assay was conducted to assess the extent of cross-reactivity between the two epitopes. The findings revealed that MS patients in the acute phase exhibited a higher specific antibody response to the pHERV-W env epitope compared to syncytin-1. This suggests a potential pathogenic role for pHERV-W env during the inflammatory stages of central nervous system involvement, and these antibody responses could serve as useful biomarkers for monitoring the progression of the disease.
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Retrovirus Endógenos , Esclerosis Múltiple , Proteínas Gestacionales , Humanos , Productos del Gen env/genética , Productos del Gen env/metabolismo , Proteínas Gestacionales/metabolismo , Anticuerpos , Retrovirus Endógenos/metabolismoRESUMEN
Syncytin-1 and -2 are glycoproteins encoded by human endogenous retrovirus (hERV) that, through their fusogenic properties, are needed for the formation of the placental syncytiotrophoblast. Previous studies suggested that these proteins, in addition to the EnvP(b) envelope protein, are also involved in other cell fusion events. Since galectin-1 is a ß-galactoside-binding protein associated with cytotrophoblast fusion during placental development, we previously tested its effect on Syncytin-mediated cell fusion and showed that this protein differently modulates the fusogenic potential of Syncytin-1 and -2. Herein, we were interested in comparing the impact of galectin-1 on hERV envelope proteins in different cellular contexts. Using a syncytium assay, we first demonstrated that galectin-1 increased the fusion of Syncytin-2- and EnvP(b)-expressing cells. We then tested the infectivity of Syncytin-1 and -2 vs. VSV-G-pseudotyped viruses toward Cos-7 and various human cell lines. In the presence of galectin-1, infection of Syncytin-2-pseudotyped viruses augmented for all cell lines. In contrast, the impact of galectin-1 on the infectivity of Syncytin-1-pseudotyped viruses varied, being cell- and dose-dependent. In this study, we report the functional associations between three hERV envelope proteins and galectin-1, which should provide information on the fusogenic activity of these proteins in the placenta and other biological and pathological processes.
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Retrovirus Endógenos , Placenta , Femenino , Humanos , Embarazo , Línea Celular , Retrovirus Endógenos/metabolismo , Galectina 1/metabolismo , Productos del Gen env/genética , Placenta/metabolismo , Trofoblastos/metabolismo , Fusión CelularRESUMEN
Cell fusion in the placenta is tightly regulated. Suppressyn is a human placental endogenous retroviral protein that inhibits the profusogenic activities of another well-described endogenous retroviral protein, syncytin-1. In this study, we aimed to elucidate the mechanisms underlying suppressyn's placenta-specific expression. We identified the promoter region and a novel enhancer region for the gene encoding suppressyn, ERVH48-1, and examined their regulation via DNA methylation and their responses to changes in the oxygen concentration. Like other endogenous retroviral genes, the ERVH48-1 promoter sequence is found within a characteristic retroviral 5' LTR sequence. The novel enhancer sequence we describe here is downstream of this LTR sequence (designated EIEs: ERV internal enhancer sequence) and governs placental expression. The placenta-specific expression of ERVH48-1 is tightly controlled by DNA methylation and further regulated by oxygen concentration-dependent, hypoxia-induced transcription factors (HIF1α and HIF2α). Our findings highlight the involvement of (1) tissue specificity through DNA methylation, (2) expression specificity through placenta-specific enhancer regions, and (3) the regulation of suppressyn expression in differing oxygen conditions by HIF1α and HIF2α. We suggest that these regulatory mechanisms are central to normal and abnormal placental development, including the development of disorders of pregnancy involving altered oxygenation, such as preeclampsia, pregnancy-induced hypertension, and fetal growth restriction.
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Retrovirus Endógenos , Trofoblastos , Femenino , Humanos , Embarazo , Fusión Celular , Retrovirus Endógenos/genética , Retrovirus Endógenos/metabolismo , Productos del Gen env/genética , Productos del Gen env/metabolismo , Oxígeno/metabolismo , Placenta/metabolismo , Trofoblastos/metabolismoRESUMEN
Human endogenous retrovirus (HERV)-K was reportedly inserted into the human genome millions of years ago and is closely related to various diseases, including cancer and immune regulation. In our previous studies, CRISPR-Cas9-enabled knockout (KO) of the HERV-K env gene was found to potentially reduce cell proliferation, cell migration, and invasion in colorectal and ovarian cancer cell lines. The immune response involves the migration and invasion of cells and is similar to cancer; however, in certain ways, it is completely unlike cancer. Therefore, we induced HERV-K119 env gene KO in THP-1, a monocytic cell that can be differentiated into a macrophage, to investigate the role of HERV-K119 env in immune regulation. Cell migration and invasion were noted to be significantly increased in HERV-K119 env KO THP-1 cells than in MOCK, and these results were contrary to those of cancer cells. To identify the underlying mechanism of HERV-K119 env KO in THP-1 cells, transcriptome analysis and cytokine array analysis were conducted. Semaphorin7A (SEMA7A), which induces the production of cytokines in macrophages and monocytic cells and plays an important role in immune effector cell activation during an inflammatory immune response, was significantly increased in HERV-K119 env KO THP-1 cells. We also found that HERV-K119 env KO THP-1 cells expressed various macrophage-specific surface markers, suggesting that KO of HERV-K119 env triggers the differentiation of THP-1 cells from monocytic cells into macrophages. In addition, analysis of the expression of M1 and M2 macrophage markers showed that M1 macrophage marker cluster of differentiation 32 (CD32) was significantly increased in HERV-K119 env KO cells. These results suggest that HERV-K119 env is implicated in the differentiation of monocytic cells into M1 macrophages and plays important roles in the immune response.
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Retrovirus Endógenos , Femenino , Humanos , Retrovirus Endógenos/genética , Retrovirus Endógenos/metabolismo , Células THP-1 , Genes env , Linfocitos/metabolismo , Diferenciación Celular , Productos del Gen env/genética , Productos del Gen env/metabolismoRESUMEN
In this review, we summarized the results of experimental and clinical studies about three human endogenous retroviruses and their products-syncytin-1, syncytin-2, and suppressyn in human physiology and pathophysiology. We summed up the described connection with various pathological processes and diseases, mainly with pregnancy-induced hypertensive diseases such as preeclampsia, oncogenesis, gestational trophoblastic disease, and multiple sclerosis. Supposed mechanisms of action and the potential of clinical applications are also described.
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Retrovirus Endógenos , Preeclampsia , Proteínas Gestacionales , Embarazo , Femenino , Humanos , Placenta , Productos del Gen env/genética , Proteínas Gestacionales/genéticaRESUMEN
Endogenous retroviruses (ERVs) are retrovirus-like sequences that were previously integrated into the host genome. Although most ERVs are inactivated by mutations, deletions, or epigenetic regulation, some remain transcriptionally active and impact host physiology. Several ERV-encoded proteins, such as Syncytins and Suppressyn, contribute to placenta acquisition, a crucial adaptation in mammals that protects the fetus from external threats and other risks while enabling the maternal supply of oxygen, nutrients, and antibodies. In primates, Syncytin-1 and Syncytin-2 facilitate cell-cell fusion for placental formation. Suppressyn is the first ERV-derived protein that inhibits cell fusion by binding to ASCT2, the receptor for Syncytin-1. Furthermore, Syncytin-2 likely inserted into the genome of the common ancestor of Anthropoidea, whereas Syncytin-1 and Suppressyn likely inserted into the ancestor of catarrhines; however, they were inactivated in some lineages, suggesting that multiple exaptation events had occurred. This review discusses the role of ERV-encoded proteins, particularly Syncytins and Suppressyn, in placental development and function, focusing on the integration of ERVs into the host genome and their contribution to the genetic mechanisms underlying placentogenesis. This review provides valuable insights into the molecular and genetic aspects of placentation, potentially shedding light on broader evolutionary and physiological processes in mammals.
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Retrovirus Endógenos , Placenta , Animales , Embarazo , Femenino , Placenta/metabolismo , Retrovirus Endógenos/genética , Retrovirus Endógenos/metabolismo , Epigénesis Genética , Placentación/genética , Productos del Gen env/genética , Productos del Gen env/metabolismo , Mamíferos/genética , Mamíferos/metabolismoRESUMEN
BACKGROUND: Human endogenous retroviruses (HERVs) entered the germ line by retroviral infection from a distant ancestor over 30 million years ago and constitute 8% of the human genome. The majorities of HERVs are non-protein coding and lack function because of the accumulation of mutations, insertions, deletions, and/or truncations. However, a small number of HERV genes carried ORFs with beneficial functions for the host. METHODS & RESULTS: In this review, we summarize the structural and important biological roles of two HERV gene products termed Syncytin-1 and Syncytin-2 in human placenta development. Indeed, two retroviral gene products that have important roles in mammalian development, Syncytin-1 (HERV-W) and Syncytin-2 (HERV-FRD), are prime examples encoded by env genes and expressed in the placental trophoblasts. Several pivotal studies revealed that Syncytins are fundamental genes implicated in regulating trophoblast fusion and placenta morphogenesis. CONCLUSION: Interestingly, it has been suggested that syncytins may also be implicated in non-fusogenic activities leading to apoptosis, proliferation, and immunosuppressive activities.
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Retrovirus Endógenos , Proteínas Gestacionales , Animales , Humanos , Embarazo , Femenino , Placenta , Retrovirus Endógenos/genética , Productos del Gen env/genética , Proteínas Gestacionales/genética , MamíferosRESUMEN
An endogenous retrovirus-derived membrane protein, syncytin (SYN), contributes to placental function via trophoblast fusion. Multinuclear trophoblasts (syncytiotrophoblasts) physically and functionally mediate the interaction between fetal and maternal vessels in various ways. Suncus murinus (suncus) is a small mammalian species with a pregnancy duration of approximately 30 days, 1.5 times longer than mice. However, the molecular basis for the longer pregnancy duration is unknown. In this study, we first isolated two genes that encoded putative SYN proteins expressed in the suncus placenta, which were named syncytin-1-like proteins 1 and 2 (SYN1L1 and SYN1L2). When their expression vectors were introduced into cultured cells, suncus SYN1L2 was found to be active in cell fusion. Moreover, the SYN1L2 protein was homologous to a SYN1-like protein identified in greater mouse-eared bats (bat SYN1L) and was structurally compared with bat SYN1L and other SYN proteins, implying the presence of structural features of the SYN1L2 protein.
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Quirópteros , Proteínas Gestacionales , Embarazo , Femenino , Animales , Placenta/metabolismo , Quirópteros/genética , Productos del Gen env/genética , Productos del Gen env/metabolismo , Proteínas Gestacionales/genética , Proteínas Gestacionales/metabolismo , MusarañasRESUMEN
Schizophrenia, a mental disorder, afflicts 1% of the worldwide population. The dysregulation of homeostasis in the endoplasmic reticulum (ER) has been implicated in schizophrenia. Moreover, recent studies indicate that ER stress and the unfolded protein response (UPR) are linked to this mental disorder. Our previous research has verified that endogenous retrovirus group W member 1 envelope (ERVW-1), a risk factor for schizophrenia, is elevated in individuals with schizophrenia. Nevertheless, no literature is available regarding the underlying relationship between ER stress and ERVW-1 in schizophrenia. The aim of our research was to investigate the molecular mechanism connecting ER stress and ERVW-1 in schizophrenia. Here, we employed Gene Differential Expression Analysis to predict differentially expressed genes (DEGs) in the human prefrontal cortex of schizophrenic patients and identified aberrant expression of UPR-related genes. Subsequent research indicated that the UPR gene called XBP1 had a positive correlation with ATF6, BCL-2, and ERVW-1 in individuals with schizophrenia using Spearman correlation analysis. Furthermore, results from the enzyme-linked immunosorbent assay (ELISA) suggested increased serum protein levels of ATF6 and XBP1 in schizophrenic patients compared with healthy controls, exhibiting a strong correlation with ERVW-1 using median analysis and Mann-Whitney U analysis. However, serum GANAB levels were decreased in schizophrenic patients compared with controls and showed a significant negative correlation with ERVW-1, ATF6, and XBP1 in schizophrenic patients. Interestingly, in vitro experiments verified that ERVW-1 indeed increased ATF6 and XBP1 expression while decreasing GANAB expression. Additionally, the confocal microscope experiment suggested that ERVW-1 could impact the shape of the ER, leading to ER stress. GANAB was found to participate in ER stress regulated by ERVW-1. In conclusion, ERVW-1 induced ER stress by suppressing GANAB expression, thereby upregulating the expression of ATF6 and XBP1 and ultimately contributing to the development of schizophrenia.
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Factor de Transcripción Activador 6 , Productos del Gen env , Glucosidasas , Esquizofrenia , Humanos , Factor de Transcripción Activador 6/genética , Factor de Transcripción Activador 6/metabolismo , Retículo Endoplásmico/metabolismo , Estrés del Retículo Endoplásmico , Esquizofrenia/genética , Transducción de Señal , Respuesta de Proteína Desplegada , Productos del Gen env/genética , Productos del Gen env/metabolismo , Glucosidasas/genética , Glucosidasas/metabolismoRESUMEN
Independently acquired envelope (env) genes from endogenous retroviruses have contributed to the placental trophoblast cell-cell fusion in therian mammals. Egg-laying mammals (monotremes) are an important sister clade for understanding mammalian placental evolution, but the env genes in their genomes have yet to be investigated. Here, env-derived open reading frames (env-ORFs) encoding more than 400 amino acid lengths were searched in the genomes of two monotremes: platypus and echidna. Only two env-ORFs were present in the platypus genome, whereas 121 env-ORFs were found in the echidna genome. The echidna env-ORFs were phylogenetically classified into seven groups named env-Tac1 to -Tac7. Among them, the env-Tac1 group contained only a single gene, and its amino acid sequence showed high similarity to those of the RD114/simian type D retroviruses. Using the pseudotyped virus assay, we demonstrated that the Env-Tac1 protein utilizes echidna sodium-dependent neutral amino acid transporter type 1 and 2 (ASCT1 and ASCT2) as entry receptors. Moreover, the Env-Tac1 protein caused cell-cell fusion in human 293T cells depending on the expression of ASCT1 and ASCT2. These results illustrate that fusogenic env genes are not restricted to placental mammals, providing insights into the evolution of retroviral genes and the placenta.
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Retrovirus Endógenos , Ornitorrinco , Tachyglossidae , Animales , Embarazo , Femenino , Humanos , Genes env , Placenta , Ornitorrinco/genética , Tachyglossidae/genética , Productos del Gen env/genética , Mamíferos/genéticaRESUMEN
Syncytin-2 is a membrane fusion protein involved in placenta development that is derived from the endogenous retrovirus envelope gene acquired in the common ancestral lineage of New World and Old World monkeys (OWMs). It is known that syncytin-2 is conserved between apes and OWMs, suggesting its functional importance; however, syncytin-2 of common marmosets (Callithrix jacchus) exhibits lower fusogenic activity than those of humans and OWMs in human cell lines. To obtain insight into the functional diversity of syncytin-2 genes in primates, we examined the syncytin-2 gene in New World monkeys (NWMs). We experimentally evaluated the cell fusion ability of syncytin-2 in humans, C. jacchus, and tufted capuchins (Sapajus apella). We found that the cell fusion ability of S. apella was lower than that of human syncytin-2. Chimeric syncytin-2 constructs revealed that the amino acid differences in the surface unit of S. apella syncytin-2 were responsible for the weak cell fusion activity. In addition, genomic sequence analyses of syncytin-2 revealed that the open reading frames (ORFs) of syncytin-2 were highly conserved in seven apes and 22 OWMs; however, the syncytin-2 ORFs of three of 12 NWM species were truncated. Our results suggest that syncytin-2 in several NWMs may be of less importance than in OWMs and apes, and other syncytin-like genes may be required for placental development in various NWM species.
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Hominidae , Placenta , Animales , Embarazo , Humanos , Femenino , Placenta/metabolismo , Platirrinos/metabolismo , Productos del Gen env/genética , Productos del Gen env/química , Productos del Gen env/metabolismo , Hominidae/metabolismoRESUMEN
Recurrent spontaneous abortion (RSA) affects approximately 5 % of women of reproductive age worldwide. The etiology and pathogenesis of approximately 50 % of RSA cases currently remain unclear, which known as unexplained RSA (URSA). Syncytin-1, an envelope protein encoded by HERV-W gene, is essential for human embryonic development. The purpose of this study was to explore the correlation between syncytin-1 expression and URSA occurrence. The villi tissues of URSA patients and patients with voluntary termination of pregnancy for non-medical reasons in early pregnancy (Control group) were collected. Compared with the Control group, syncytin-1 was abnormally low expressed in URSA villus tissues, and the HERV-W gene promoter was hypermethylated. Compared with the control group, the global DNA methylation level and the expression level of DNA methylases in the villus tissues of the URSA group had no significant difference. In addition, compared with the Control group, URSA villus tissue showed obviously abnormal apoptosis. Overexpression of syncytin-1 promoted the proliferation of HTR-8 cells and inhibited their apoptosis; while knockdown of syncytin-1 inhibited cell proliferation and promoted cell apoptosis. URSA villus tissue exhibited hypermethylation of the HERV-W gene and down-regulation of syncytin-1 expression. Syncytin-1 has the potential to be a predictive and diagnostic biomarker for URSA.
Asunto(s)
Aborto Habitual , Aborto Espontáneo , Embarazo , Humanos , Femenino , Aborto Espontáneo/metabolismo , Metilación de ADN , Aborto Habitual/patología , Productos del Gen env/genética , Productos del Gen env/metabolismo , ADN/metabolismoRESUMEN
The human endogenous retroviruses type W family envelope (HERV-W env) gene is located on chromosome 7q21-22. Our previous studies show that HERV-W env is elevated in schizophrenia and HERV-W env can increase calcium influx. Additionally, the 5-HTergic system and particularly 5-hydroxytryptamine (5-HT) receptors play a prominent role in the pathogenesis and treatment of schizophrenia. 5-hydroxytryptamine receptor 4 (5-HT4R) agonist can block calcium channels. However, the underlying relationship between HERV-W env and 5-HT4R in the etiology of schizophrenia has not been revealed. Here, we used enzyme-linked immunosorbent assay to detect the concentration of HERV-W env and 5-HT4R in the plasma of patients with schizophrenia and we found that there were decreased levels of 5-HT4R and a negative correlation between 5-HT4R and HERV-W env in schizophrenia. Overexpression of HERV-W env decreased the transcription and protein levels of 5-HT4R but increased small conductance Ca2+-activated K+ type 2 channels (SK2) expression levels. Further studies revealed that HERV-W env could interact with 5-HT4R. Additionally, luciferase assay showed that an essential region (-364 to -176 from the transcription start site) in the SK2 promoter was required for HERV-W env-induced SK2 expression. Importantly, 5-HT4R participated in the regulation of SK2 expression and promoter activity. Electrophysiological recordings suggested that HERV-W env could increase SK2 channel currents and the increase of SK2 currents was inhibited by 5-HT4R. In conclusion, HERV-W env could activate SK2 channels via decreased 5-HT4R, which might exhibit a novel mechanism for HERV-W env to influence neuronal activity in schizophrenia.