Suppressyn localization and dynamic expression patterns in primary human tissues support a physiologic role in human placentation

Abstract

We previously identified suppressyn (SUPYN), a placental protein that negatively regulates the cell fusion essential for trophoblast syncytialization via binding to the trophoblast receptor for syncytin-1, ASCT2, and hypothesized that SUPYN may thereby regulate cell-cell fusion in the placenta. Here, we redefine in vivo SUPYN localization using specific monoclonal antibodies in a rare early placental sample, showing SUPYN localization in villous and extravillous trophoblast subtypes, the decidua and even in placental debris in the maternal vasculature. In human trophoblast cell lines, we show SUPYN alters ASCT2 glycosylation within the secretory pathway and that this binding is associated with inhibition of cell fusion. Using newly-optimized trophoblast isolation protocols that allow tracking of ex vivo cell fusion, we present transcription and translation dynamics of fusion-related proteins over 96 hours in culture and the effects of changes in ambient oxygen levels on these processes. We report converse syncytin-1 and SUPYN transcriptional and translational responses to surrounding oxygen concentrations that suggest both are important in the effects of hypoxia and hyperoxia on placental syncytialization. Our results suggest that SUPYN’s anti-fusogenic properties may be exerted at several sites in the maternal body and its dysregulation may be associated with diseases of abnormal placentation.

Evolution and antiviral activity of a human protein of retroviral origin

“…as previously reported 5,[16][17][18] . To confirm these transcriptomic observations, we performed immunostaining of second (21w gestation) and third (31w gestation) trimester placenta with SUPYN antibody.…”

The Immunology of Syncytialized Trophoblast

“…Still, most of the coding sequences of the ERVs have undergone mutations that rendered their protein products non-functional. A few ERV-encoded genes, however, have retained expression of envelope (env)-derived proteins that have retained functional fusogenic properties [87][88][89][90]. The placentally expressed ERV-derived fusogens, syncytin 1 (ERVW-1), syncytin 2 (ERVFRD-1) and endogenous retrovirus 3-1 (ERV3-1) and the anti-fusogen ERVRH48-1 (suppressyn/SUPYN) are some of the best studied of these proteins.…”

“…Infection by one member of this interference family interferes with superinfection by other family members via alterations in the expression level of the shared host cell surface receptor and receptor glycosylation status; the latter affects its specificity in various cells [100]. SUPYN binding to ASCT2 alters receptor glycosylation and has been shown to inhibit interaction with the HERV-W env-derived HERVW-1 [90,98]. A very similar effect has been reported for a protein product of the fv4 gene in the env domain of murine leukemia virus (MuLV), which increases cellular resistance to superinfection with MuLV [100].…”

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

“…Two HERV proteins, syncytin-1 (syn1; ERVW-1) and syncytin-2 (syn2; ERVFRD1) and their receptors, solute-linked carrier family A member 5 (SLC1A5, aka ASCT2) and major facilitator superfamily domain-containing protein 2 (MFSD2), respectively, have been specifically implicated in fusion events [ 11 , 12 , 13 , 14 ]. We have recently described a third placental HERV protein, called suppressyn (SUPYN), that inhibits the profusogenic activity of syn1, but not syn2, in a dose-dependent fashion in in vitro models of CTB fusion [ 15 , 16 ].…”

“…Suppressyn is a truncated envelope protein derived from the HERV-H family of viruses ( ERVH48-1 ) that is expressed at multiple sites in the placenta, including the CTB, and to a lesser extent the STB, of the floating villi, in the intermediate CTB of the anchoring villi, in invasive EVT (extravillous cytotrophoblast cells) within the decidua and in the endovascular trophoblast (endoTB) lining the maternal decidual vessels [ 15 , 16 , 17 ]. Since both cell-associated and secreted forms of suppressyn bind to SLC1A5, the cell surface receptor for syn1 [ 15 ], we have hypothesized that the anti-fusogenic effects of suppressyn on syn1-induced trophoblast fusion occur at the level of this shared binding partner.…”