RESUMO
Syncytin-1 and envPb1 are two conserved envelope genes in the human genome encoded by single loci from the HERV-W and -Pb families, respectively. To characterize the role of these envelope proteins in cell-cell fusion, we have developed lentiviral vectors that express short hairpin RNAs for stable knockdown of syncytin-1 and envPb1. Analysis of heterotypic fusion activity between trophoblast-derived choriocarcinoma BeWo cells, in which syncytin-1 and envPb1 are specifically silenced, and endothelial cells demonstrated that both syncytin-1 and envPb1 are important to fusion. The ability to fuse cells makes syncytin-1 and envPb1 attractive candidate molecules in therapy against cancer. Our available vectors may help eventually to decipher roles for these genes in human health and/or disease.
Assuntos
Coriocarcinoma/metabolismo , Produtos do Gene env/metabolismo , Inativação Gênica , Proteínas Nucleares/metabolismo , Proteínas da Gravidez/metabolismo , Retroviridae/genética , Fatores de Transcrição/metabolismo , Fusão Celular , Células Cultivadas , Proteínas de Ligação a DNA , Células Endoteliais , Evolução Molecular , Técnicas de Silenciamento de Genes , Produtos do Gene env/genética , Humanos , Proteínas Nucleares/genética , Proteínas da Gravidez/genética , Fatores de Transcrição/genéticaRESUMO
We have investigated the role of human endogenous retroviruses in multiple sclerosis by analyzing the DNA of patients and controls in 4 cohorts for associations between multiple sclerosis and polymorphisms near viral restriction genes or near endogenous retroviral loci with one or more intact or almost-intact genes. We found that SNPs in the gene TRIM5 were inversely correlated with disease. Conversely, SNPs around one retroviral locus, HERV-Fc1, showed a highly significant association with disease. The latter association was limited to a narrow region that contains no other known genes. We conclude that HERV-Fc1 and TRIM5 play a role in the etiology of multiple sclerosis. If these results are confirmed, they point to new modes of treatment for multiple sclerosis.
Assuntos
Retrovirus Endógenos/genética , Retrovirus Endógenos/fisiologia , Esclerose Múltipla/etiologia , Alelos , Estudos de Casos e Controles , Estudos de Coortes , DNA Viral/análise , DNA Viral/fisiologia , Feminino , Predisposição Genética para Doença , Heterozigoto , Humanos , Desequilíbrio de Ligação , Masculino , Esclerose Múltipla/genética , Esclerose Múltipla/virologia , Razão de Chances , Polimorfismo de Nucleotídeo Único/fisiologiaRESUMO
BACKGROUND: Most human endogenous retroviruses (HERVs) invaded our genome at least 25 million years ago. The majority of the viral genes are degenerated, since no selection preserves them within the genome. However, a few intact and very old HERV genes exist, and likely are beneficial for the host. We here address evolutionary aspects of two HERV-V envelope genes, ENVV1 and ENVV2, located in tandem and containing a long open reading frame. RESULTS: The ENVV2 gene is preserved with an intact reading frame during simian evolution, but none of the ENVV genes are found in the prosimian species tested. While we observe many transposon insertions in the gag and pol regions of the ERV-V2 provirus, the ENVV2 genes have escaped transposon crossfire in all species tested. Additional analysis of nucleotide substitutions provides further strong evidence of purifying selection on the ENVV2 gene during primate evolution. The other copy, ENVV1, seems to be involved in gene conversion of the major part of the envelope. Furthermore, ENVV1 and ENVV2 show placenta-specific expression in human and a baboon species. CONCLUSION: Our analyses show that ERV-V entered our genome after the split between simian and prosimian primates. Subsequent purifying selection and gene conversion have preserved two copies of the ENVV envelope gene in most species. This is the first case of gene conversion involving long open reading frames in HERVs. Together with the placenta-specific expression of the human and baboon ENVV1 and ENVV2 envelope genes, these data provide strong evidence of a beneficial role for the host.