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.
Highlights
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
Using an optimized anti-SUPYN monoclonal antibody (Supplementary Fig. S1) and a very rare tissue sample from a woman at 7 weeks of gestation who underwent elective hysterectomy for cervical cancer with her pregnancy in situ, we refined our understanding of SUPYN localization and confirmed prior descriptions of HLA-G, cytokeratin 7 (CK7) and known human placental fusogens and their partners in early gestation (Fig. 1)
HLA-G was confirmed as a specific marker for extravillous cytotrophoblast cells (EVTs) and the monolayer epithelial cell marker CK7 was present in cytotrophoblast, intermediate cytotrophoblast, EVT and endometrial glandular epithelium[19]
Summary
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. Syncytin-1 (SYN1)[8] and syncytin-2 (SYN2)[9] are truncated envelope (env) proteins from two distinct and unrelated human endogenous retroviruses (HERVs) that would have originally allowed for viral fusion with target host cells Both retroviruses are thought to have infected host germ cells many millions of years ago. A select few, have been co-opted for known physiologic function and the fusion-inducing function of SYN1 and SYN2 appear to have been maintained under selective pressure in a tissue specific fashion during the evolution of the human placenta[11,12] This cooptation of viral fusogens into the placenta has been a decidedly successful strategy, as an ever-increasing group of species has been shown to use virally-derived env proteins during placental development. Our results support an in vivo role for SUPYN in normal and abnormal placental development
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