On the same side: VISTA and its ligands interact in cis on the cell surface
Karina Smorodinsky-Atias1, Gil Wiseglass1, Alina Artyukhova1
1School of Neurobiology, Biochemistry and Biophysics, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
Protein Science : a Publication of the Protein Society
|December 22, 2025
Summary
VISTA, an immune checkpoint protein, binds ligands in cis (same cell), not trans (between cells). This discovery clarifies VISTA
Area of Science:
- Immunology
- Molecular Biology
- Cell Biology
Background:
- VISTA is a critical immune checkpoint protein regulating T-cell function and tolerance.
- Understanding VISTA's binding mechanism is crucial for developing anti-tumor and autoimmune therapies.
- Previous studies lacked clarity on VISTA's membrane orientation and ligand interaction mode.
Purpose of the Study:
- To elucidate the binding mode and membrane orientation of VISTA.
- To investigate whether VISTA interacts with its ligands in trans or cis.
- To provide a framework for developing novel VISTA-targeted therapeutics.
Main Methods:
- Cell aggregation assays to assess trans interactions.
- MicroScale Thermophoresis (MST) and flow cytometry for soluble VISTA binding.
- Split luciferase complementation assays for membrane-tethered VISTA interactions.
- Cancer Genome Atlas data analysis for co-expression patterns.
Main Results:
- VISTA does not interact with ligands in a trans manner.
- Soluble VISTA binds ligands, but membrane-bound VISTA's orientation restricts trans interactions.
- Membrane-tethered VISTA exhibits cis interactions with its ligands.
- Strong VISTA and PSGL-1 co-expression correlation observed in cancer data.
- VISTA's Ig domain likely orients towards the membrane, favoring cis interactions.
Conclusions:
- VISTA primarily interacts with its ligands in cis, on the same cell.
- This cis interaction suggests an intrinsic VISTA signaling pathway.
- The findings clarify VISTA's mechanism, enabling targeted therapeutic development.
- The study presents a novel experimental platform for VISTA drug discovery.
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