Endogenization of retroviruses has occurred multiple times in the course of vertebrate evolution, with the captured retroviral envelope syncytins playing a role in placentation in mammals, including marsupials. Here, we identify an endogenous retroviral envelope protein with unprecedented properties, including a specific cleavage process resulting in the shedding of its extracellular moiety in the human blood circulation. This protein is conserved in all simians—with a homologous protein found in marsupials—with a “stemness” expression in embryonic and reprogrammed stem cells, as well as in the placenta and some human tumors, especially ovarian tumors. This protein could constitute a versatile marker—and possibly an effector—of specific cellular states and being shed, be immunodetected in the blood.

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 (medium-reiteration-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.