HEMO, an ancestral endogenous retroviral envelope protein shed in the blood of pregnant women and expressed in pluripotent stem cells and tumors

Abstract

Capture of retroviral envelope genes is likely to have played a role in the emergence of placental mammals, with evidence for multiple, reiterated, and independent capture events occurring in mammals, and be responsible for the diversity of present day placental structures. Here, we uncover a full-length endogenous retrovirus envelope protein, dubbed HEMO [human endogenous MER34 (mediumreiteration-frequency-family-34) ORF], with unprecedented characteristics, because it is actively shed in the blood circulation in humans via specific cleavage of the precursor envelope protein upstream of the transmembrane domain. At variance with previously identified retroviral envelope genes, its encoding gene is found to be transcribed from a unique CpG-rich promoter not related to a retroviral LTR, with sites of expression including the placenta as well as other tissues and rather unexpectedly, stem cells as well as reprogrammed induced pluripotent stem cells (iPSCs), where the protein can also be detected. We provide evidence that the associated retroviral capture event most probably occurred >100 Mya before the split of Laurasiatheria and Euarchontoglires, with the identified retroviral envelope gene encoding a full-length protein in all simians under purifying selection and with similar shedding capacity. Finally, a comprehensive screen of the expression of the gene discloses high transcript levels in several tumor tissues, such as germ cell, breast, and ovarian tumors, with in the latter case, evidence for a histotype dependence and specific protein expression in clear-cell carcinoma. Altogether, the identified protein could constitute a "stemness marker" of the normal cell and a possible target for immunotherapeutic approaches in tumors.HERV | endogenous retrovirus | envelope protein | placenta | development | stem cells | tumors E ndogenous retroviral sequences represent ∼8% of the human genome. These sequences [called human endogenous retroviruses (HERVs)] share strong similarities with present day retroviruses and are the proviral remnants of ancestral germ-line infections by active retroviruses, which have thereafter been transmitted in a Mendelian manner (1-3). The >30,000 proviral copies found in the human genome can be grouped into about 80 distinct families, with most of these elements being nonprotein-coding because of the accumulation of mutations, insertions, deletions, and/or truncations (4, 5). However, some retroviral genes have retained a coding capacity, and some of them have even been diverted by remote primate ancestors for a physiological role. The so-called "syncytins," namely syncytin-1 and -2 in humans, are retroviral envelope (env) genes captured 25 and 40 Mya, respectively, with a full-length proteincoding sequence, a fusogenic activity, and strong placental expression (6-9). These genes have been shown to be involved in placenta formation, with their fusogenic activity contributing to the formation of the syncytiotrophoblast (ST) at the maternofetal interface as a result of the syncytin-mediated...

Diverse endogenous retroviruses generate structural variation between human genomes via LTR recombination

“…Conceivably then, variation in the copy number of HERV-encoded genes caused by sporadic LTR recombination events, either in the germline or in somatic cells, could modulate susceptibility to these pathologies. Importantly, three of the dimorphic HERV-K loci predicted herein (Table1 , Table S2) are known to encode full-length env proteins (88). Thus, our results reveal a previously underappreciated source of HERV gene copy number variation with potential pathological ramifications.…”

“…Previously identified: ☽ insertion polymorphism (pre-integration allele for the provirus) has been identified in (27). Presence of Refseq / LINC RNA / envORF: *env encodes a complete envelope gene of > 400 amino acids according to Heidmann et al (88). Expression type in hiPSCells: MA: moderately active, HA: Highly active, Expression type of full length HERVH identified in hiPSC lines and single cells derived from three individual hESC clones (60).…”

The ancient fusogen EnvP(b)1 is expressed in human tissues and its structure informs the evolution of gammaretrovirus envelope proteins

“…HERV-T is no longer processed, is not fusogenic and has evolved to downregulate its receptor (19). HEMO, of unknown function, is not classically processed by proteases but has evolved to be shed from cells via an alternative cleavage event (20). Others, like recently integrated HERV-K copies, may have been too recently acquired to have gained or lost functions.…”

Immune Regulation in Eutherian Pregnancy: Live Birth Coevolved with Novel Immune Genes and Gene Regulation

“…Apart from syncytins, genome‐wide searches for ERV Env proteins have uncovered 45 Env‐encoding open reading frames, one of them encoding an unusual Env protein, HEMO of the MER34 family, which is lacking several characteristics shared among other Env proteins . Unlike other Env proteins, HEMO does not possess fusogenic properties and is shed into the local and peripheral blood in pregnant women.…”

“…Unlike other Env proteins, HEMO does not possess fusogenic properties and is shed into the local and peripheral blood in pregnant women. While the exact role of HEMO in pregnancy is yet unknown, it is speculated that the shed HEMO proteins may act to sequester receptors that could be used by other retroviruses, thereby aiding host defense activities . While the exact roles in reproduction are yet unknown, there are other examples of ERV‐derived genes (and proteins) expressed in the placenta.…”