From ancestral infectious retroviruses to bona fide cellular genes: Role of the captured syncytins in placentation

Unité des Rétrovirus Endogènes et Éléments Rétroïdes des Eucaryotes Supérieurs, CNRS, UMR 8122, Institut Gustave Roussy, 114 rue Édouard Vaillant, 94805 Villejuif, France.
Placenta (Impact Factor: 2.71). 06/2012; 33(9):663-71. DOI: 10.1016/j.placenta.2012.05.005
Source: PubMed


During their replication, infectious retroviruses insert a reverse-transcribed cDNA copy of their genome, a "provirus", into the genome of their host. If the infected cell belongs to the germline, the integrated provirus can become "fixed" within the host genome as an endogenous retrovirus and be transmitted vertically to the progeny in a Mendelian fashion. Based on the numerous proviral sequences that are recovered within the genomic DNA of vertebrates--up to ten percent in the case of mammals--such events must have occurred repeatedly during the course of millions of years of evolution. Although most of the ancient proviral sequences have been disrupted, a few "endogenized" retroviral genes are conserved and still encode functional proteins. In this review, we focus on the recent discovery of genes derived from the envelope glycoprotein-encoding (env) genes of endogenous retroviruses that have been domesticated by mammals to carry out an essential function in placental development. They were called syncytins based on the membrane fusogenic capacity that they have kept from their parental env gene and which contributes to the formation of the placental fused cell layer called the syncytiotrophoblast, at the materno-fetal interface. Remarkably, the capture of syncytin or syncytin-like genes, sometimes as pairs, was found to have occurred independently from different endogenous retroviruses in diverse mammalian lineages such as primates--including humans--, muroids, leporids, carnivores, caviids, and ovis, between around 10 and 85 million years ago. Knocking out one or both mouse syncytin-A and -B genes provided evidence that they indeed play a critical role in placentation. We discuss the possibility that the immunosuppressive domain embedded within retroviral envelope glycoproteins and conserved in syncytin proteins, may be involved in the tolerance of the fetus by the maternal immune system. Finally, we speculate that the capture of a founding syncytin-like gene could have been instrumental in the dramatic transition from egg-laying to placental mammals.

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Available from: Anne Dupressoir, Oct 12, 2015
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    • "It has been hypothesised that maintenance of the encoding ability of endogenous retroviruses may have important roles, e.g., maintenance of physiological functions during reproduction, pathophysiological negative effects in cancer (Prudhomme et al., 2005; Jern and Coffin, 2008) or protection against exogenous retroviruses at the entry level by inducing cellular resistance to exogenous viruses through receptor interference (Ikeda and Sugimura, 1989; Ponferrada et al., 2003) or during retroviral replication (Pryciak and Varmus, 1992). The endogenous Jaagsiekte Sheep RetroViruses are essential for placental development in sheep as shown for independently acquired endogenous retroviruses in humans or rodents (Taruscio and Mantovani, 2004; Prudhomme et al., 2005; Dunlap et al., 2006; Dupressoir et al., 2012; Lavialle et al., 2013). A role, if any, of them in cancer development is not clearly identified. "
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    ABSTRACT: Sheep and goats are widely infected by oncogenic retroviruses, namely Jaagsiekte Sheep RetroVirus (JSRV) and Enzootic Nasal Tumour Virus (ENTV). Under field conditions, these viruses induce transformation of differentiated epithelial cells in the lungs for Jaagsiekte Sheep RetroVirus or the nasal cavities for Enzootic Nasal Tumour Virus. As in other vertebrates, a family of endogenous retroviruses named endogenous Jaagsiekte Sheep RetroVirus (enJSRV) and closely related to exogenous Jaagsiekte Sheep RetroVirus is present in domestic and wild small ruminants. Interestingly, Jaagsiekte Sheep RetroVirus and Enzootic Nasal Tumour Virus are able to promote cell transformation, leading to cancer through their envelope glycoproteins. In vitro, it has been demonstrated that the envelope is able to deregulate some of the important signaling pathways that control cell proliferation. The role of the retroviral envelope in cell transformation has attracted considerable attention in the past years, but it appears to be highly dependent of the nature and origin of the cells used. Aside from its health impact in animals, it has been reported for many years that the Jaagsiekte Sheep RetroVirus-induced lung cancer is analogous to a rare, peculiar form of lung adenocarcinoma in humans, namely lepidic pulmonary adenocarcinoma. The implication of a retrovirus related to Jaagsiekte Sheep RetroVirus is still controversial and under investigation, but the identification of an infectious agent associated with the development of lepidic pulmonary adenocarcinomas might help us to understand cancer development. This review explores the mechanisms of induction of respiratory cancers in small ruminants and the possible link between retrovirus and lepidic pulmonary adenocarcinomas in humans.
    Full-text · Article · Sep 2015 · Veterinary Microbiology
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    • "A good documented evolutionary example would be the Kat1 gene of the yeast Kluyveromyces, which participates in mating type switching and is derived from a transposition event at the base of this genus (Rajaei et al. 2014). In mammalian evolution, envelope genes of ERVs have been converted to syncytin genes (essential for placenta formation) multiple times (Dupressoir et al. 2012). And quite spectacularly, Drosophila telomeres are believed to be maintained by repurposed non-LTR retrotransposon reverse transcriptases (Belfort et al. 2011). "
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    ABSTRACT: One of several issues at play in the renewed debate over "junk DNA" is the organizational level at which genomic features might be seen as selected, and thus to exhibit function, as etiologically defined. The intuition frequently expressed by molecular geneticists that junk DNA is functional because it serves to "speed evolution" or as an "evolutionary repository" could be recast as a claim about selection between species (or clades) rather than within them, but this is not often done. Here we review general arguments for the importance of selection at levels above that of organisms in evolution, and develop them further for a common genomic feature: the carriage of transposable elements (TEs). In many species, not least our own, TEs comprise a large fraction of all nuclear DNA, and whether they individually or collectively contribute to fitness - or are instead junk - is a subject of ongoing contestation. Even if TEs generally owe their origin to selfish selection at the lowest level (that of genomes), their prevalence in extant organisms and the prevalence of extant organisms bearing them must also respond to selection within species (on organismal fitness) and between species (on rates of speciation and extinction). At an even higher level, the persistence of clades may be affected (positively or negatively) by TE carriage. If indeed TEs speed evolution, it is at these higher levels of selection that such a function might best be attributed to them as a class. © The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.
    Full-text · Article · Aug 2015 · Genome Biology and Evolution
    • "A well-studied example of this is the case of the HERV-W and HERV-FRD env genes, which encode the proteins syncytin-1 and syncytin-2, respectively (Dupressoir et al., 2012). These proteins are required for placenta formation, allowing fusion of cells to form the syncytiotrophoblast and contributing to immune tolerance of the fetus (Dupressoir et al., 2012). In addition, genes and regulatory sequences from ERVs have been co-opted in the fight against viral infections, providing endogenous viral-element-derived immunity (Aswad & Katzourakis, 2012). "
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    ABSTRACT: The human genome comprises 8 % endogenous retroviruses (ERVs), the majority of which are defective due to deleterious mutations. Nonetheless, transcripts of ERVs are found in most tissues, and these transcripts could either be reverse transcribed to generate ssDNA or expressed to generate proteins. Thus, the expression of ERVs could produce nucleic acids or proteins with viral signatures, much like the pathogen-associated molecular patterns of exogenous viruses, which would enable them to be detected by the innate immune system. The activation of some pattern recognition receptors (PRRs) in response to ERVs has been described in mice and in the context of human autoimmune diseases. Here, we review the evidence for detection of ERVs by PRRs and the resultant activation of innate immune signalling. This is an emerging area of research within the field of innate antiviral immunity, showing how ERVs could initiate immune signalling pathways and might have implications for numerous inflammatory diseases. © 2015 The Authors.
    No preview · Article · Dec 2014 · Journal of General Virology
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