Eukaryotic genomes are littered with sequences of diverse viral origins, termed endogenous viral elements (EVEs). Here we used examples primarily drawn from mammalian endogenous retroviruses to document how the influx of EVEs has provided a source of prefabricated coding and regulatory sequences that were formerly utilized for viral infection and replication, but have been occasionally repurposed for cellular function. While EVE co-option has benefited a variety of host biological functions, there appears to be a disproportionate contribution to immunity and antiviral defense. The mammalian embryo and placenta offer opportunistic routes of viral transmission to the next host generation and as such they represent hotbeds for EVE cooption. Based on these observations, we propose that EVE cooption is initially driven as a mean to mitigate conflicts between host and viruses, which in turn acts as a stepping-stone toward the evolution of cellular innovations serving host physiology and development.
Endogenous retroviruses are abundant components of mammalian genomes descended from ancient germline infections. In several mammals, the envelope proteins encoded by these elements protect against exogenous viruses, but this activity has not been documented with endogenously expressed envelopes in humans. We report that the human genome harbors a large pool of envelope-derived sequences with the potential to restrict retroviral infection. To test this, we characterized an envelope-derived protein, Suppressyn. We found that Suppressyn is expressed in human preimplantation embryos and developing placenta using its ancestral retroviral promoter. Cell culture assays showed that Suppressyn , and its hominoid orthologs, could restrict infection by extant mammalian type D retroviruses. Our data support a generalizable model of retroviral envelope co-option for host immunity and genome defense.
SummaryViruses circulating in wild and domestic animals pose a constant threat to human health1. Identifying human genetic factors that protect against zoonotic infections is a health priority. The RD-114 and Type-D retrovirus (RDR) interference group includes infectious viruses that circulate in domestic cats and various Old World monkeys (OWM), and utilize ASCT2 as a common target cell receptor2. While human ASCT2 can mediate RDR infection in cell culture, it is unknown whether humans and other hominoids encode factors that restrict RDR infection in nature2,3. Here we test the hypothesis that Suppressyn, a truncated envelope protein that binds ASCT2 and is derived from a human endogenous retrovirus4,5, restricts RDR infection. Transcriptomics and regulatory genomics reveal that Suppressyn expression initiates in the preimplantation embryo. Loss and gain of function experiments in cell culture show Suppressyn expression is necessary and sufficient to restrict RDR infection. Evolutionary analyses show Suppressyn was acquired in the genome of a common ancestor of hominoids and OWMs, but preserved by natural selection only in hominoids. Restriction assays using modern primate orthologs and reconstructed ancestral genes indicate that Suppressyn antiviral activity has been conserved in hominoids, but lost in most OWM. Thus in humans and other hominoids, Suppressyn acts as a restriction factor against retroviruses with zoonotic capacity. Transcriptomics data predict that other virus-derived proteins with potential antiviral activity lay hidden in the human genome.
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