Laboratory of Viral and Cellular Genetics, Institute of Molecular Genetics of the Czech Academy of Sciences, Vídeňská 14220, Czech Republic.
CZ-OpenScreen National Infrastructure for Chemical Biology, Institute of Molecular Genetics of the Czech Academy of Sciences, Vídeňská 14220, Czech Republic.
Proc Natl Acad Sci U S A. 2024 Oct 29;121(44):e2407519121. doi: 10.1073/pnas.2407519121. Epub 2024 Oct 21.
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 and 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.
Syncytin-1 是一种源自逆转录病毒的人类融合蛋白，对胎盘合胞滋养层的形成至关重要。为了介导细胞间融合，Syncytin-1 需要与同源受体的特异性相互作用。两种三聚体跨膜蛋白，丙氨酸、丝氨酸、半胱氨酸转运蛋白 1 和 2（ASCT1 和 ASCT2）被认为是 Syncytin-1 的细胞受体，并被广泛接受。为了定量评估人类 ASCT1 和 ASCT2 对 Syncytin-1 融合活性的个体贡献，我们开发了一种模型系统，其中 和 双敲除通过外源性表达 ASCT1 或 ASCT2 来挽救。我们证明 ASCT2 是 Syncytin-1 结合、细胞进入和细胞间融合所必需的，而 ASCT1 不参与这种受体相互作用。我们通过实验验证了 ASCT1-ASCT2 异三聚体作为先前错误鉴定 ASCT1 为 Syncytin-1 受体的可能解释。这种受体特异性的重新定义对于正确理解 Syncytin-1 在正常和病理性妊娠中的功能非常重要。
