Syncytin-1, a human fusogenic protein of retroviral origin, is crucial for placental syncytiotrophoblast formation. To mediate cell-to-cell fusion, Syncytin-1 requires specific interaction with its cognate receptor. Two trimeric transmembrane proteins, Alanine, Serine, Cysteine Transporters 1 and 2 (ASCT1 and ASCT2), were suggested and widely accepted as Syncytin-1 cellular receptors. To quantitatively assess the individual contributions of human ASCT1 and ASCT2 to the fusogenic activity of Syncytin-1, we developed a model system where the ASCT1 and ASCT2 double knockout was rescued by ectopic expression of either ASCT1 or ASCT2. We demonstrated that ASCT2 was required for Syncytin-1 binding, cellular entry, and cell-to-cell fusion, while ASCT1 was not involved in this receptor interaction. We experimentally validated the ASCT1-ASCT2 heterotrimers as a possible explanation for the previous misidentification of ASCT1 as a receptor for Syncytin-1. This redefinition of receptor specificity is important for proper understanding of Syncytin-1 function in normal and pathological pregnancy.

• Keywords
• Syncytin-1, cell-to-cell fusion, endogenous retrovirus, placenta, viral receptor,
• MeSH
• Fusion Regulatory Protein 1, Heavy Chain MeSH
• Cell Fusion * MeSH
• Gene Products, env * metabolism   genetics   MeSH
• Humans MeSH
• Placenta * metabolism   MeSH
• Pregnancy Proteins * metabolism   genetics   MeSH
• Pregnancy MeSH
• Amino Acid Transport System ASC * metabolism   genetics   MeSH
• Amino Acid Transport Systems, Neutral metabolism   genetics   MeSH
• Trophoblasts metabolism   cytology   MeSH
• Minor Histocompatibility Antigens metabolism   genetics   MeSH
• Check Tag
• Humans MeSH
• Pregnancy MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Fusion Regulatory Protein 1, Heavy Chain MeSH
• Gene Products, env * MeSH
• SLC1A5 protein, human MeSH Browser
• SLC3A2 protein, human MeSH Browser
• syncytin MeSH Browser
• Pregnancy Proteins * MeSH
• Amino Acid Transport System ASC * MeSH
• Amino Acid Transport Systems, Neutral MeSH
• Minor Histocompatibility Antigens MeSH