How ancient retroviruses shaped our placenta and may help fight cancer

Millions of years ago, certain retroviruses integrated their genetic material into our ancestors’ genomes. Instead of causing harm, these viral genes have been co-opted to perform critical functions in human biology. Two such genes originating from ancient retroviruses now encode for human syncytin-1 and suppressyn proteins, which play crucial roles in cell-cell fusion at the maternal-fetal interface in the placenta.

Syncytin-1: This protein is essential for the formation of the syncytiotrophoblast, a layer of fused cells in the placenta that facilitates nutrient exchange between mother and fetus. Derived from the human endogenous retrovirus W (HERV-W), syncytin-1 retains the ability to fuse membranes, a trait inherited from its viral origins.

Suppressyn: Originating from a different retrovirus (HERV-H), suppressyn lacks the ability to fuse membranes but instead acts as a regulator. It inhibits syncytin-1’s fusogenic activity, ensuring proper placental development.

Both syncytin-1 and suppressyn function through binding to the common cellular receptor, the neutral amino acid transporter ASCT2 (SLC1 family of amino acid transporters). However, the molecular mechanisms underlying the recognition of ASCT2 by these retroviral proteins have remained unknown.

Recent research sheds light on how these proteins interact with and inhibit the ASCT2 receptor. Using cryo-electron microscopy, researchers showed that despite evolutionary differences, both proteins bind to and occupy similar positions on ASCT2 and are stabilized by a hybrid β-sheet structure, or “clamp.”

This structural insight reveals how these proteins and various retroviruses compete for the same binding site on ASCT2, which has significant implications: suppressyn’s ability to block syncytin-1 and other retroviruses from binding to ASCT2 suggests it plays a role in immune defense. By occupying ASCT2, suppressyn can prevent certain retroviruses from entering and infecting cells.

Interestingly, using SSM-based electrophysiology (SURFE2R), the authors showed that syncytin-1 and suppressyn act as partial inhibitors of ASCT2 transport, which may lead to significant outcomes.

ASCT2 is critical for amino acid transport and is upregulated in various cancers, making it a potential target for therapy. Despite ongoing efforts to develop small-molecule compounds, no potent and selective ASCT2 transport inhibitors have been reported. By designing molecules that mimic syncytin-1 and suppressyn, researchers could create selective inhibitors to block ASCT2, potentially starving cancer cells of the amino acids they need to grow.

Overall, this research not only enhances our understanding of placental biology but also opens new avenues for innovative anticancer therapies.

Find the original article here: https://www.nature.com/articles/s41594-024-01295-6

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