Could the Human Endogenous Retrovirus-Derived Syncytialization Inhibitor, Suppressyn, Limit Heterotypic Cell Fusion Events in the Decidua?

Abstract

Proper placental development relies on tightly regulated trophoblast differentiation and interaction with maternal cells. Human endogenous retroviruses (HERVs) play an integral role in modulating cell fusion events in the trophoblast cells of the developing placenta. Syncytin-1 (ERVW-1) and its receptor, solute-linked carrier family A member 5 (SLC1A5/ASCT2), promote fusion of cytotrophoblast (CTB) cells to generate the multi-nucleated syncytiotrophoblast (STB) layer which is in direct contact with maternal blood. Another HERV-derived protein known as Suppressyn (ERVH48-1/SUPYN) is implicated in anti-fusogenic events as it shares the common receptor with ERVW-1. Here, we explore primary tissue and publicly available datasets to determine the distribution of ERVW-1, ERVH48-1 and SLC1A5 expression at the maternal-fetal interface. While SLC1A5 is broadly expressed in placental and decidual cell types, ERVW-1 and ERVH48-1 are confined to trophoblast cell types. ERVH48-1 displays higher expression levels in CTB and extravillous trophoblast, than in STB, while ERVW-1 is generally highest in STB. We have demonstrated through gene targeting studies that suppressyn has the ability to prevent ERVW-1-induced fusion events in co-culture models of trophoblast cell/maternal endometrial cell interactions. These findings suggest that differential HERV expression is vital to control fusion and anti-fusogenic events in the placenta and consequently, any imbalance or dysregulation in HERV expression may contribute to adverse pregnancy outcomes.

Involvement of the HERV-derived cell-fusion inhibitor, suppressyn, in the fusion defects characteristic of the trisomy 21 placenta

“…In humans, the human endogenous retrovirus (HERV) protein, syncytin-1 (syn-1; aka ERVW-1 ) is necessary for the fusion of CTB into STB in the chorionic villus 10 . We have identified and reported on the presence of an endogenous inhibitor of cytotrophoblast cell fusion that is also derived from the env of an endogenous retrovirus 13 – 15 . Named suppressyn (SUPYN; aka ERVH48-1 ), this HERV-derived anti-fusogen is a 160 amino acid polypeptide that contains a stop codon upstream of the region encoding the transmembrane segment of an otherwise typical retroviral env 15 .…”

LncRNA ERVH48-1 Contributes to the Drug Resistance of Prostate Cancer and Proliferation through Sponging of miR-4784 to the Activation of the Wnt/β-Catenin Pathway

“…This mechanism has been the subject of a substantial amount of research [ 27 ] as a result of the frequency with which microRNAs are sponged and repressed by lncRNAs operating as ceRNAs. According to the findings of an integrated bioinformatic study, the gene WNT2B [ 25 ], which is responsible for ERVH48-targeting 1, has miR-4784 as one of its direct targets.…”

Human Endogenous Retroviruses: Friends and Foes in Urology Clinics

“…• HERV1: Homologous recombination • Disrupting EYA1 gene in rats [55] • HERV signatures associated with ccRCC prognosis [52] Uterus (female) • SYN-1, SYN-2, SUPYN in placenta [2,3,11,132,133] • HERVs in endometria and pregnancy [135][136][137][138][139][140][141] Prostate (male) • HERV-K (HML-2) [33] • HERV transcription profiles [38][39][40][41] • Irradiation [35] and Arsenic [36] • RT inhibitors [37] • RNase L and OAS [13] Fig. 1.…”

“…Syn-1 and Syn-2 bind their respective receptors, ASCT-2 (sodium-dependent neutral amino acid transporter type 2, aka solute-linked carrier family A member 5 [SLC1A5]) and domain-containing protein 2a (MFSD2a) in human trophoblasts, inducing fusion of individual trophoblast cells into a multinucleated layer of syncytiotrophoblasts, which form an outer layer of placental villi and in direct contact with maternal blood flow [ 51 ]. Suppressyn (SUPYN) is a truncated ENV protein encoded by the HERVH48-1 env gene from a HERV-H family virus, which interferes with cell-cell fusion [ 132 , 133 ]. ERVMER34-1 is another HERV-derived protein, which is also expected to negatively regulate cell fusion in cytotrophoblast [ 134 ].…”