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

Abstract

Suppressyn (SUPYN) is the first host-cell encoded mammalian protein shown to inhibit cell–cell fusion. Its expression is restricted to the placenta, where it negatively regulates syncytia formation in villi. Since its chromosomal localization overlaps with the Down syndrome critical region and the TS21 placenta is characterized by delayed maturation of cytotrophoblast cells and reduced syncytialization, we hypothesized a potential link between changes in SUPYN expression and morphologic abnormalities in the TS21 placenta. Here we demonstrate that an increase in chromosomal copy number in the TS21 placenta is associated with: (1) reduced fusion of cytotrophoblast cells into syncytiotrophoblast in vivo, (2) increased SUPYN transcription, translation and secretion in vivo, (3) increased SUPYN/syncytin-1 receptor degradation in vivo, (4) increased SUPYN transcription and secretion ex vivo, (5) decreased cytotrophoblast cell fusion ex vivo, and (6) reciprocal response of changes in SUPYN and CGB in TS21 placental cells ex vivo. These data suggest direct links between immature placentation in Down syndrome and increased SUPYN. Finally, we report a significant increase in secreted SUPYN concentration in maternal serum in women with pregnancies affected by Down syndrome, suggesting that SUPYN may be useful as an alternate or additional diagnostic marker for this disease.

Evolution and antiviral activity of a human protein of retroviral origin

“…This result suggests that if SUPYN acts by receptor interference, its interaction with ASCT2 leads to partial receptor degradation, which is consistent with some instances of receptor interference ( 22 , 23 ). In agreement with previous observations ( 6 , 24 ), we noted that SUPYN knockdown in Jar cells resulted in selective loss of a putative unglycosylated isoform of ASCT2 (fig. S11, B to D).…”

Acquisition and Exaptation of Endogenous Retroviruses in Mammalian Placenta

“…In trisomy 21 placenta, the number of Suppressyn-positive cytotrophoblasts increased, and the expression level of Suppressyn per cytotrophoblast also increased [19]. The expression level of Suppressyn in the serum is elevated in trisomy 21, resulting in excessive suppression of placental formation and immature placenta [19].…”

“…In addition, cell-cell fusion is disrupted in the placenta of trisomy 21 (Down syndrome) owing to the abnormal expression of Syncytin-2, resulting in dysplasia of the syncytiotrophoblast [112,113]. In trisomy 21 placenta, the number of Suppressyn-positive cytotrophoblasts increased, and the expression level of Suppressyn per cytotrophoblast also increased [19]. The expression level of Suppressyn in the serum is elevated in trisomy 21, resulting in excessive suppression of placental formation and immature placenta [19].…”

“…Syncytin proteins are encoded by modified env genes of ERVs. The Syncytin family, identified in various animals, was linked to placental dysfunction observed in preeclampsia, intrauterine growth retardation (IGR), and Down syndrome [14][15][16][17][18][19]. In this review, we aimed to consolidate the existing knowledge on the evolution of placental morphogenesis and physiology.…”

Intrinsic signalling factors associated with cancer cell-cell fusion

“…In the course of placenta formation Sugimoto and colleagues demonstrated that the human endogenous retroviral (HERV) element suppressyn impaired syncytin-1-mediated cytotrophoblast fusion by binding to the syncytin-1 receptor alanine, serine, cysteine transporter 2 (ASCT2) [ 79 ]. Moreover, increased suppressyn serum levels were found in women with placental defects in Down syndrome pregnancies [ 80 ]. In fact, a disturbed or dysregulated trophoblast syncytialization during placentation is commonly associated with an impaired maintenance and failed integrity of the blood-placental barrier.…”