PMID:28739914

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

HEMO is the oldest known captured full-length env gene in the human genome (>100 million years)
Expressed in placental trophoblasts, stem cells, and tumors
Secreted form detected in blood of pregnant women
Released by specific cleavage upstream of the transmembrane domain
Driven by cellular CpG-rich promoter (not related to a retroviral LTR)
Gene shows evidence of purifying selection in all simians

PMID:25421890

Implication of human endogenous retrovirus envelope proteins in placental functions.

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping

file:human/ERVMER34-1/ERVMER34-1-deep-research-cyberian.md

Cyberian deep research report on ERVMER34-1/HEMO

HEMO interacts with BACE2, an interaction acquired in the primate lineage ~30-45 MYA
BACE2 interaction arose through mutations that introduced new cysteines and eliminated furin cleavage site
Retains immunosuppressive domain (ISD) despite loss of fusogenic capacity
Expression in tumors associated with Wnt/beta-catenin pathway activation
CTNNB1 mutations found in 73.6% of HEMO-expressing endometrial cancers vs 1.9% in HEMO-negative
Squamous cell carcinomas show particularly high HEMO expression
Proposed as cancer biomarker and therapeutic target

file:human/ERVMER34-1/ERVMER34-1-deep-research-falcon.md

Falcon (Edison Scientific Literature) deep research report on ERVMER34-1/HEMO

HEMO is a 563-aa Env-like precursor with N-terminal signal peptide, SU CWLC motif, TM ISD-like region and C-X6-CC motif, 23-aa transmembrane helix, and cytoplasmic tail
Canonical furin cleavage motif is mutated to CTQG and an adjacent hydrophobic fusion peptide is absent
Ectodomain shedding is metalloproteinase-mediated (ADAM/MMP), inhibited by Batimastat, Marimastat, and GM6001 at ~0.1-10 uM
Mature shed form begins at residue 27; mass spectrometry mapped C-terminal cleavage primarily at Q432 and R433 (~4:1 ratio)
Membrane anchoring is required for efficient shedding (TM-truncated constructs are not efficiently shed)
Major cell-associated SU-TM form ~58 kDa and major shed/soluble form ~48 kDa
No fusogenic activity has been detected experimentally
No HEMO host receptor or validated signaling pathway is currently established
HEMO is transcribed from a CpG-rich, non-LTR host-like promoter under DNA methylation control; >500-fold activity in luciferase assays
ISD-like sequence motif is present but direct immunosuppressive activity for HEMO has not been demonstrated
Expressed predominantly in first-trimester villous cytotrophoblasts and extravillous trophoblasts, with diffuse syncytiotrophoblast staining
Inducible by gamma-irradiation in HNSCC cell lines and proposed as a pan-cancer immunotherapy target

PMID:37892164

Acquisition and Exaptation of Endogenous Retroviruses in Mammalian Placenta

ERVMER34-1/HEMO is expressed in cytotrophoblasts and extravillous trophoblasts in the first gestation and is detected in the blood of pregnant females
ERVMER34-1 has no fusion activity and its function is unknown; localization similar to ERVH48-1/Suppressyn motivates an anti-cell-fusion hypothesis
ERVMER34-1 was retained in Laurasian and Eurasian theropods, entering the Boreoeutheria genome ~100-120 MYA, with the ORF conserved in all simians and cats

PMID:36979914

HERVs and Cancer - A Comprehensive Review of the Relationship of Human Endogenous Retroviruses and Human Cancers

HEMO (MER34-derived Env) proposed by Heidmann et al. 2017 as a possible marker for ovarian clear-cell carcinoma with histotype dependence
ERV3-1 and ERVMER34-1 env induced upon exposure of HNSCC cell lines to gamma-radiation - potential target to overcome radioresistance
HEMO envelope gene "hailed as a pan-cancer target" across many solid tumors and leukemias