Decoding the Mechanism of Action of a Parasite TGFβ Antagonist Inspires the Creation of Cell-Type-Specific TGFβ Modulators
Heligmosomoides polygyrus, a mouse parasite, modulates host immunity by secreting modular transforming growth factor-β (TGFβ) mimics (TGMs). The agonist TGM1 interacts with TGFBR1, TGFBR2, and the co-receptor CD44 through domains D1/2, D3, and D4/5, respectively. In contrast, the antagonist TGM6, wh...
| Autores: | , , , , , , , , , |
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| Tipo de recurso: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2026 |
| País: | España |
| Institución: | Universidad de Sevilla (US) |
| Repositorio: | idUS. Depósito de Investigación de la Universidad de Sevilla |
| OAI Identifier: | oai:dnet:idus________::1470d3e900eda530a02c79b504cff6c6 |
| Acceso en línea: | https://hdl.handle.net/11441/186445 https://doi.org/10.1002/advs.75322 |
| Access Level: | acceso abierto |
| Palabra clave: | Betaglycan Bispecific antibodies Heligmosomoides polygyrus Lipoprotein receptor-related protein Molecular mimicry Signal transduction Transforming growth factor-β |
| Sumario: | Heligmosomoides polygyrus, a mouse parasite, modulates host immunity by secreting modular transforming growth factor-β (TGFβ) mimics (TGMs). The agonist TGM1 interacts with TGFBR1, TGFBR2, and the co-receptor CD44 through domains D1/2, D3, and D4/5, respectively. In contrast, the antagonist TGM6, which lacks D1/2, but retains TGFBR2 binding through D3, targets different cells compared to TGM1. The TGM6 co-receptor is unknown. Using X-ray crystallography and binding studies, we show that TGM6 preferentially binds mouse TGFBR2 over human TGFBR2, and that this is essential for its antagonistic function. We identified low-density lipoprotein receptor-related protein 1 (LRP1) and betaglycan (TGFBR3) as co-receptors for TGM6. LRP1 enhances TGM6 efficacy and is required for its antagonistic effect by promoting TGFBR2 lysosomal degradation, whereas betaglycan counteracts TGM6 in a TGFBR2-dependent manner. The modular organization of TGMs enabled us to design TGM1/6 chimeras or TGM-D3 fusion with an affibody that recognizes a specific cell-surface receptor, thereby altering cell-type specificity and functionality. Furthermore, we developed a TGFBR2 nanobody that, on its own, has no inhibitory effect but, when fused to a receptor antibody, antagonizes TGFβ by blocking TGFβ receptor interaction in a cell-selective manner. Thus, we designed programmable agents that modulate TGFβ signaling only in co-receptor-expressing cells. |
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