Evolution and antiviral activity of a human protein of retroviral origin

Abstract

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.

Unique Structure and Distinctive Properties of the Ancient and Ubiquitous Gamma-Type Envelope Glycoprotein

“…Because their origins and underlying virological functions are well understood, ERV-encoded Env glycoproteins can serve as model systems for understanding the phenomenon of evolutionary cooption and the events that occur after germline integration of an env gene, such as acquisition and fine-tuning of host-cell regulatory mechanisms, integration within the regulatory networks of other interacting host genes, and further adaptations of the encoded Env protein for optimal host function [ 25 , 27 ]. For example, decades of work on exogenous viruses such as MLV-guided identification of the fusion defects in the murine Fv4 and human envHERV-T viral resistance proteins [ 66 , 69 , 72 ]).…”

“…Ancient endogenous retrovirus (ERV) loci often contain remnants of retroviral env genes, and in some cases, these may retain complete or nearly complete open reading frames with the potential to express functional gamma-type Env proteins [ 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 ]. Gammaretrovirus-related ERV loci are abundant in the genomes of a diverse array of vertebrate species, including mammals, birds/reptiles and amphibians [ 28 , 29 , 30 , 31 , 32 ].…”

“…As with many other vertebrates, the human genome contains a multitude of ERV loci, some of which retain some or all of the associated env ORF [ 25 , 27 , 70 ]. Proving that these have, or once had, antiviral functions is challenging.…”

“…Among other things, the exogenous forms of the related viruses may have gone extinct millions of years ago. Experimentally, it has been shown that two human ERV-encoded gamma-type Envs (Suppressyn and Syncytin-1/HERV-W) that bind the ASCT2 receptor (SLC1A5) can also induce receptor-interference and render cells resistant to infection by extant retroviruses of other primates that also use ASCT2 as an entry receptor [ 25 , 71 ]. Another strategy is to use ERV sequence information to reconstruct the proteins of an extinct virus, allowing a direct test of the receptor-interference hypothesis.…”

Delivering mRNAs to mouse tissues using the SEND system

“…Further, the receptor for SynA, lymphocyte antigen 6 family member E (Ly6e), is highly expressed in murine spleen (in addition to liver, lung, and placenta) and mediates cell-cell fusion upon binding with SynA, [18][19][20] which suggests that fusogens like SynA and SynB could be involved in SEND-VLP phenomenon in spleen but again our experiments may not have been sensitive enough to detect it. In addition, recent studies have reported several genes that reduce cell-cell fusion efficiency of endogenous retroviral envelope genes by interfering their receptors in humans 21,22 and various primates. 23 While no interfering elements have been reported for SynA and SynB, they may also be involved in transduction efficiency.…”