TGM6 is a helminth secretory product that mimics TGF-β binding to TGFBR2 to antagonize signaling in fibroblasts

Stephen E. White, Tristin A. Schwartze, Ananya Mukundan, Christina Schoenherr, Shashi P. Singh, Maarten Dinther, Kyle T. Cunningham, Madeleine P. J. White, Tiffany Campion, John Pritchard, Cynthia S. Hinck, Peter Dijke, Gareth J. Inman, Rick M. Maizels and Andrew P. Hinck (ahinck@pitt.edu)
Additional contact information
Stephen E. White: University of Pittsburgh School of Medicine
Tristin A. Schwartze: University of Pittsburgh School of Medicine
Ananya Mukundan: University of Pittsburgh School of Medicine
Christina Schoenherr: University of Glasgow
Shashi P. Singh: University of Glasgow
Maarten Dinther: University of Leiden
Kyle T. Cunningham: University of Glasgow
Madeleine P. J. White: University of Glasgow
Tiffany Campion: University of Glasgow
John Pritchard: University of Glasgow
Cynthia S. Hinck: University of Pittsburgh School of Medicine
Peter Dijke: University of Leiden
Gareth J. Inman: University of Glasgow
Rick M. Maizels: University of Glasgow
Andrew P. Hinck: University of Pittsburgh School of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract TGM6 is a natural antagonist of mammalian TGF-β signaling produced by the murine helminth parasite Heligmosomoides polygyrus. It differs from the previously described agonist, TGM1 (TGF-β Mimic-1), in that it lacks domains 1/2 that bind TGFBR1. It nonetheless retains TGFBR2 binding through domain 3 and potently inhibits TGF-β signaling in fibroblasts and epithelial cells, but does not inhibit TGF-β signaling in T cells, consistent with divergent domains 4/5 and an altered co-receptor binding preference. The crystal structure of TGM6 bound to TGFBR2 reveals an interface remarkably similar to that of TGF-β with TGFBR2. Thus, TGM6 has adapted its structure to mimic TGF-β, while engaging a distinct co-receptor to direct antagonism to fibroblasts and epithelial cells. The co-expression of TGM6, along with immunosuppressive TGMs that activate the TGF-β pathway, may minimize fibrotic damage to the host as the parasite progresses through its life cycle from the intestinal lumen to submucosa and back again. The co-receptor-dependent targeting of TGFBR2 by the parasite provides a template for the development of therapies for targeting the cancer- and fibrosis-promoting activities of the TGF-βs in humans.

Date: 2025
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DOI: 10.1038/s41467-025-56954-z

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