TGM6 is a helminth secretory product that mimics TGF-β binding to TGFBR2 to antagonize signaling in fibroblasts
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.
Authors
- Cynthia S. Hinck (ORCID: https://orcid.org/0000-0002-2163-9378)
- Rick M. Maizels (ORCID: https://orcid.org/0000-0003-3216-1944)
- Maarten van Dinther (ORCID: https://orcid.org/0000-0002-9451-8884)
- Gareth J. Inman (ORCID: https://orcid.org/0000-0002-6264-4253)
- Tiffany Campion (ORCID: https://orcid.org/0009-0002-4010-0762)
- John Pritchard (ORCID: https://orcid.org/0000-0002-1812-6985)
- Kyle T. Cunningham (ORCID: https://orcid.org/0000-0002-2171-0277)
- Andrew P. Hinck (ORCID: https://orcid.org/0000-0003-3320-8054)
- Christina Schoenherr (ORCID: https://orcid.org/0000-0002-0983-6168)
- Shashi Prakash Singh (ORCID: https://orcid.org/0000-0002-6029-8115)
- Peter ten Dijke (ORCID: https://orcid.org/0000-0002-7234-342X)
- Ananya Mukundan (ORCID: https://orcid.org/0000-0003-1161-4158)
- Stephen E. White (ORCID: https://orcid.org/0000-0002-7786-4400)
- Tristin A. Schwartze
- Madeleine P. J. White (ORCID: https://orcid.org/0000-0002-0152-1110)
Institutions
- University of Pittsburgh (US)
- Cancer Research UK (GB)
- Wellcome Centre for Molecular Parasitology (GB)
- Oncode Institute (NL)
- United Therapeutics (United States) (US)
- Birla Institute of Technology and Science, Pilani (IN)
- University of Glasgow (GB)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-02-21
- DOI
- https://doi.org/10.1038/s41467-025-56954-z
- Citations
- 7
- Primary Topic
- TGF-β signaling in diseases
- Type
- article
- Field-Weighted Citation Impact
- 5.64
Funders
- Wellcome
- Division of Intramural Research, National Institute of Allergy and Infectious Diseases
- Wellcome Trust
- Cancer Research UK
- National Institutes of Health
- University of California, San Francisco
- National Institute of General Medical Sciences
- Argonne National Laboratory