Decoding the Mechanism of Action of a Parasite TGFβ Antagonist Inspires the Creation of Cell‐Type‐Specific TGFβ Modulators

ABSTRACT 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.