White, Stephen E. and Schwartze, Tristin A. and Mukundan, Ananya and Schoenherr, Christina and Singh, Shashi P. and van Dinther, Maarten and Cunningham, Kyle T. and White, Madeleine P. J. and Campion, Tiffany and Pritchard, John and Hinck, Cynthia S. and ten Dijke, Peter and Inman, Gareth J. and Maizels, Rick M. and Hinck, Andrew P. (2025) TGM6 is a helminth secretory product that mimics TGF-β binding to TGFBR2 to antagonize signaling in fibroblasts. Nature Communications, 16 (1): 1847. ISSN 2041-1723

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.

People
White, Stephen E.
Author

White, Stephen E. and Schwartze, Tristin A. and Mukundan, Ananya and Schoenherr, Christina and Singh, Shashi P. and van Dinther, Maarten and Cunningham, Kyle T. and White, Madeleine P. J. and Campion, Tiffany and Pritchard, John and Hinck, Cynthia S. and ten Dijke, Peter and Inman, Gareth J. and Maizels, Rick M. and Hinck, Andrew P. (2025) TGM6 is a helminth secretory product that mimics TGF-β binding to TGFBR2 to antagonize signaling in fibroblasts. Nature Communications, 16 (1): 1847. ISSN 2041-1723

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Schwartze, Tristin A.
Author

White, Stephen E. and Schwartze, Tristin A. and Mukundan, Ananya and Schoenherr, Christina and Singh, Shashi P. and van Dinther, Maarten and Cunningham, Kyle T. and White, Madeleine P. J. and Campion, Tiffany and Pritchard, John and Hinck, Cynthia S. and ten Dijke, Peter and Inman, Gareth J. and Maizels, Rick M. and Hinck, Andrew P. (2025) TGM6 is a helminth secretory product that mimics TGF-β binding to TGFBR2 to antagonize signaling in fibroblasts. Nature Communications, 16 (1): 1847. ISSN 2041-1723

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Mukundan, Ananya
Author

White, Stephen E. and Schwartze, Tristin A. and Mukundan, Ananya and Schoenherr, Christina and Singh, Shashi P. and van Dinther, Maarten and Cunningham, Kyle T. and White, Madeleine P. J. and Campion, Tiffany and Pritchard, John and Hinck, Cynthia S. and ten Dijke, Peter and Inman, Gareth J. and Maizels, Rick M. and Hinck, Andrew P. (2025) TGM6 is a helminth secretory product that mimics TGF-β binding to TGFBR2 to antagonize signaling in fibroblasts. Nature Communications, 16 (1): 1847. ISSN 2041-1723

Singh, Shashi P. and Smyth, Danielle J. and Cunningham, Kyle T. and Mukundan, Ananya and Byeon, Chang-Hyeock and Hinck, Cynthia S. and White, Madeleine P.J. and Ciancia, Claire and Wąsowska, Natalia and Sanders, Anna and Jin, Regina and White, Ruby F. and Lilla, Sergio and Zanivan, Sara and Schoenherr, Christina and Inman, Gareth and van Dinther, Maarten and ten Dijke, Peter and Hinck, Andrew P. and Maizels, Rick M. (2025) The TGF-β mimic TGM4 achieves cell specificity through combinatorial surface co-receptor binding. EMBO Reports, 26 (1). pp. 218-244. ISSN 1469-221X

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Schoenherr, Christina
Author

White, Stephen E. and Schwartze, Tristin A. and Mukundan, Ananya and Schoenherr, Christina and Singh, Shashi P. and van Dinther, Maarten and Cunningham, Kyle T. and White, Madeleine P. J. and Campion, Tiffany and Pritchard, John and Hinck, Cynthia S. and ten Dijke, Peter and Inman, Gareth J. and Maizels, Rick M. and Hinck, Andrew P. (2025) TGM6 is a helminth secretory product that mimics TGF-β binding to TGFBR2 to antagonize signaling in fibroblasts. Nature Communications, 16 (1): 1847. ISSN 2041-1723

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Singh, Shashi P.
Author

White, Stephen E. and Schwartze, Tristin A. and Mukundan, Ananya and Schoenherr, Christina and Singh, Shashi P. and van Dinther, Maarten and Cunningham, Kyle T. and White, Madeleine P. J. and Campion, Tiffany and Pritchard, John and Hinck, Cynthia S. and ten Dijke, Peter and Inman, Gareth J. and Maizels, Rick M. and Hinck, Andrew P. (2025) TGM6 is a helminth secretory product that mimics TGF-β binding to TGFBR2 to antagonize signaling in fibroblasts. Nature Communications, 16 (1): 1847. ISSN 2041-1723

Singh, Shashi P. and Smyth, Danielle J. and Cunningham, Kyle T. and Mukundan, Ananya and Byeon, Chang-Hyeock and Hinck, Cynthia S. and White, Madeleine P.J. and Ciancia, Claire and Wąsowska, Natalia and Sanders, Anna and Jin, Regina and White, Ruby F. and Lilla, Sergio and Zanivan, Sara and Schoenherr, Christina and Inman, Gareth and van Dinther, Maarten and ten Dijke, Peter and Hinck, Andrew P. and Maizels, Rick M. (2025) The TGF-β mimic TGM4 achieves cell specificity through combinatorial surface co-receptor binding. EMBO Reports, 26 (1). pp. 218-244. ISSN 1469-221X

See full publications list
van Dinther, Maarten
Author

White, Stephen E. and Schwartze, Tristin A. and Mukundan, Ananya and Schoenherr, Christina and Singh, Shashi P. and van Dinther, Maarten and Cunningham, Kyle T. and White, Madeleine P. J. and Campion, Tiffany and Pritchard, John and Hinck, Cynthia S. and ten Dijke, Peter and Inman, Gareth J. and Maizels, Rick M. and Hinck, Andrew P. (2025) TGM6 is a helminth secretory product that mimics TGF-β binding to TGFBR2 to antagonize signaling in fibroblasts. Nature Communications, 16 (1): 1847. ISSN 2041-1723

Singh, Shashi P. and Smyth, Danielle J. and Cunningham, Kyle T. and Mukundan, Ananya and Byeon, Chang-Hyeock and Hinck, Cynthia S. and White, Madeleine P.J. and Ciancia, Claire and Wąsowska, Natalia and Sanders, Anna and Jin, Regina and White, Ruby F. and Lilla, Sergio and Zanivan, Sara and Schoenherr, Christina and Inman, Gareth and van Dinther, Maarten and ten Dijke, Peter and Hinck, Andrew P. and Maizels, Rick M. (2025) The TGF-β mimic TGM4 achieves cell specificity through combinatorial surface co-receptor binding. EMBO Reports, 26 (1). pp. 218-244. ISSN 1469-221X

See full publications list
Cunningham, Kyle T.
Author

White, Stephen E. and Schwartze, Tristin A. and Mukundan, Ananya and Schoenherr, Christina and Singh, Shashi P. and van Dinther, Maarten and Cunningham, Kyle T. and White, Madeleine P. J. and Campion, Tiffany and Pritchard, John and Hinck, Cynthia S. and ten Dijke, Peter and Inman, Gareth J. and Maizels, Rick M. and Hinck, Andrew P. (2025) TGM6 is a helminth secretory product that mimics TGF-β binding to TGFBR2 to antagonize signaling in fibroblasts. Nature Communications, 16 (1): 1847. ISSN 2041-1723

Singh, Shashi P. and Smyth, Danielle J. and Cunningham, Kyle T. and Mukundan, Ananya and Byeon, Chang-Hyeock and Hinck, Cynthia S. and White, Madeleine P.J. and Ciancia, Claire and Wąsowska, Natalia and Sanders, Anna and Jin, Regina and White, Ruby F. and Lilla, Sergio and Zanivan, Sara and Schoenherr, Christina and Inman, Gareth and van Dinther, Maarten and ten Dijke, Peter and Hinck, Andrew P. and Maizels, Rick M. (2025) The TGF-β mimic TGM4 achieves cell specificity through combinatorial surface co-receptor binding. EMBO Reports, 26 (1). pp. 218-244. ISSN 1469-221X

See full publications list
White, Madeleine P.J.
Author

White, Stephen E. and Schwartze, Tristin A. and Mukundan, Ananya and Schoenherr, Christina and Singh, Shashi P. and van Dinther, Maarten and Cunningham, Kyle T. and White, Madeleine P. J. and Campion, Tiffany and Pritchard, John and Hinck, Cynthia S. and ten Dijke, Peter and Inman, Gareth J. and Maizels, Rick M. and Hinck, Andrew P. (2025) TGM6 is a helminth secretory product that mimics TGF-β binding to TGFBR2 to antagonize signaling in fibroblasts. Nature Communications, 16 (1): 1847. ISSN 2041-1723

Singh, Shashi P. and Smyth, Danielle J. and Cunningham, Kyle T. and Mukundan, Ananya and Byeon, Chang-Hyeock and Hinck, Cynthia S. and White, Madeleine P.J. and Ciancia, Claire and Wąsowska, Natalia and Sanders, Anna and Jin, Regina and White, Ruby F. and Lilla, Sergio and Zanivan, Sara and Schoenherr, Christina and Inman, Gareth and van Dinther, Maarten and ten Dijke, Peter and Hinck, Andrew P. and Maizels, Rick M. (2025) The TGF-β mimic TGM4 achieves cell specificity through combinatorial surface co-receptor binding. EMBO Reports, 26 (1). pp. 218-244. ISSN 1469-221X

See full publications list
Campion, Tiffany
Author

White, Stephen E. and Schwartze, Tristin A. and Mukundan, Ananya and Schoenherr, Christina and Singh, Shashi P. and van Dinther, Maarten and Cunningham, Kyle T. and White, Madeleine P. J. and Campion, Tiffany and Pritchard, John and Hinck, Cynthia S. and ten Dijke, Peter and Inman, Gareth J. and Maizels, Rick M. and Hinck, Andrew P. (2025) TGM6 is a helminth secretory product that mimics TGF-β binding to TGFBR2 to antagonize signaling in fibroblasts. Nature Communications, 16 (1): 1847. ISSN 2041-1723

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Pritchard, John
Author

White, Stephen E. and Schwartze, Tristin A. and Mukundan, Ananya and Schoenherr, Christina and Singh, Shashi P. and van Dinther, Maarten and Cunningham, Kyle T. and White, Madeleine P. J. and Campion, Tiffany and Pritchard, John and Hinck, Cynthia S. and ten Dijke, Peter and Inman, Gareth J. and Maizels, Rick M. and Hinck, Andrew P. (2025) TGM6 is a helminth secretory product that mimics TGF-β binding to TGFBR2 to antagonize signaling in fibroblasts. Nature Communications, 16 (1): 1847. ISSN 2041-1723

See full publications list
Hinck, Cynthia S.
Author

White, Stephen E. and Schwartze, Tristin A. and Mukundan, Ananya and Schoenherr, Christina and Singh, Shashi P. and van Dinther, Maarten and Cunningham, Kyle T. and White, Madeleine P. J. and Campion, Tiffany and Pritchard, John and Hinck, Cynthia S. and ten Dijke, Peter and Inman, Gareth J. and Maizels, Rick M. and Hinck, Andrew P. (2025) TGM6 is a helminth secretory product that mimics TGF-β binding to TGFBR2 to antagonize signaling in fibroblasts. Nature Communications, 16 (1): 1847. ISSN 2041-1723

Singh, Shashi P. and Smyth, Danielle J. and Cunningham, Kyle T. and Mukundan, Ananya and Byeon, Chang-Hyeock and Hinck, Cynthia S. and White, Madeleine P.J. and Ciancia, Claire and Wąsowska, Natalia and Sanders, Anna and Jin, Regina and White, Ruby F. and Lilla, Sergio and Zanivan, Sara and Schoenherr, Christina and Inman, Gareth and van Dinther, Maarten and ten Dijke, Peter and Hinck, Andrew P. and Maizels, Rick M. (2025) The TGF-β mimic TGM4 achieves cell specificity through combinatorial surface co-receptor binding. EMBO Reports, 26 (1). pp. 218-244. ISSN 1469-221X

See full publications list
ten Dijke, Peter
Author

White, Stephen E. and Schwartze, Tristin A. and Mukundan, Ananya and Schoenherr, Christina and Singh, Shashi P. and van Dinther, Maarten and Cunningham, Kyle T. and White, Madeleine P. J. and Campion, Tiffany and Pritchard, John and Hinck, Cynthia S. and ten Dijke, Peter and Inman, Gareth J. and Maizels, Rick M. and Hinck, Andrew P. (2025) TGM6 is a helminth secretory product that mimics TGF-β binding to TGFBR2 to antagonize signaling in fibroblasts. Nature Communications, 16 (1): 1847. ISSN 2041-1723

Singh, Shashi P. and Smyth, Danielle J. and Cunningham, Kyle T. and Mukundan, Ananya and Byeon, Chang-Hyeock and Hinck, Cynthia S. and White, Madeleine P.J. and Ciancia, Claire and Wąsowska, Natalia and Sanders, Anna and Jin, Regina and White, Ruby F. and Lilla, Sergio and Zanivan, Sara and Schoenherr, Christina and Inman, Gareth and van Dinther, Maarten and ten Dijke, Peter and Hinck, Andrew P. and Maizels, Rick M. (2025) The TGF-β mimic TGM4 achieves cell specificity through combinatorial surface co-receptor binding. EMBO Reports, 26 (1). pp. 218-244. ISSN 1469-221X

See full publications list
Inman, Gareth
Author

White, Stephen E. and Schwartze, Tristin A. and Mukundan, Ananya and Schoenherr, Christina and Singh, Shashi P. and van Dinther, Maarten and Cunningham, Kyle T. and White, Madeleine P. J. and Campion, Tiffany and Pritchard, John and Hinck, Cynthia S. and ten Dijke, Peter and Inman, Gareth J. and Maizels, Rick M. and Hinck, Andrew P. (2025) TGM6 is a helminth secretory product that mimics TGF-β binding to TGFBR2 to antagonize signaling in fibroblasts. Nature Communications, 16 (1): 1847. ISSN 2041-1723

Singh, Shashi P. and Smyth, Danielle J. and Cunningham, Kyle T. and Mukundan, Ananya and Byeon, Chang-Hyeock and Hinck, Cynthia S. and White, Madeleine P.J. and Ciancia, Claire and Wąsowska, Natalia and Sanders, Anna and Jin, Regina and White, Ruby F. and Lilla, Sergio and Zanivan, Sara and Schoenherr, Christina and Inman, Gareth and van Dinther, Maarten and ten Dijke, Peter and Hinck, Andrew P. and Maizels, Rick M. (2025) The TGF-β mimic TGM4 achieves cell specificity through combinatorial surface co-receptor binding. EMBO Reports, 26 (1). pp. 218-244. ISSN 1469-221X

Smith, Craig D.L. and McMahon, Alex D. and Purkayastha, Mitana and Creaney, Grant and Clements, Kelten and Inman, Gareth J. and Bhatti, Lesley A. and Douglas, Catriona M. and Paterson, Claire and Conway, David I. (2024) Head and neck cancer incidence is rising but the sociodemographic profile is unchanging: a population epidemiological study (2001-2020). BJC Reports, 2: 71. ISSN 2731-9377

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Maizels, Rick M.
Author

White, Stephen E. and Schwartze, Tristin A. and Mukundan, Ananya and Schoenherr, Christina and Singh, Shashi P. and van Dinther, Maarten and Cunningham, Kyle T. and White, Madeleine P. J. and Campion, Tiffany and Pritchard, John and Hinck, Cynthia S. and ten Dijke, Peter and Inman, Gareth J. and Maizels, Rick M. and Hinck, Andrew P. (2025) TGM6 is a helminth secretory product that mimics TGF-β binding to TGFBR2 to antagonize signaling in fibroblasts. Nature Communications, 16 (1): 1847. ISSN 2041-1723

Singh, Shashi P. and Smyth, Danielle J. and Cunningham, Kyle T. and Mukundan, Ananya and Byeon, Chang-Hyeock and Hinck, Cynthia S. and White, Madeleine P.J. and Ciancia, Claire and Wąsowska, Natalia and Sanders, Anna and Jin, Regina and White, Ruby F. and Lilla, Sergio and Zanivan, Sara and Schoenherr, Christina and Inman, Gareth and van Dinther, Maarten and ten Dijke, Peter and Hinck, Andrew P. and Maizels, Rick M. (2025) The TGF-β mimic TGM4 achieves cell specificity through combinatorial surface co-receptor binding. EMBO Reports, 26 (1). pp. 218-244. ISSN 1469-221X

See full publications list
Hinck, Andrew P.
Author

White, Stephen E. and Schwartze, Tristin A. and Mukundan, Ananya and Schoenherr, Christina and Singh, Shashi P. and van Dinther, Maarten and Cunningham, Kyle T. and White, Madeleine P. J. and Campion, Tiffany and Pritchard, John and Hinck, Cynthia S. and ten Dijke, Peter and Inman, Gareth J. and Maizels, Rick M. and Hinck, Andrew P. (2025) TGM6 is a helminth secretory product that mimics TGF-β binding to TGFBR2 to antagonize signaling in fibroblasts. Nature Communications, 16 (1): 1847. ISSN 2041-1723

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Title:
TGM6 is a helminth secretory product that mimics TGF-β binding to TGFBR2 to antagonize signaling in fibroblasts
Creators:
White, Stephen E. and Schwartze, Tristin A. and Mukundan, Ananya and Schoenherr, Christina and Singh, Shashi P. and van Dinther, Maarten and Cunningham, Kyle T. and White, Madeleine P. J. and Campion, Tiffany and Pritchard, John and Hinck, Cynthia S. and ten Dijke, Peter and Inman, Gareth J. and Maizels, Rick M. and Hinck, Andrew P.
Identification Number:
10.1038/s41467-025-56954-z
Date:
21 February 2025
Divisions:
College of Medical Veterinary and Life Sciences > School of Cancer Sciences
College of Medical Veterinary and Life Sciences > School of Infection & Immunity
Publisher:
Nature Research
Additional Information:
This research was supported by the NIH through an RO1 (GM58670) and RO3 (AI53915) awarded to A.H. and an F30 (AI157069) awarded to A.M. and the Wellcome Trust through an Investigator Award (Ref 219530) to R.M.M., Discovery Award to P.tD., R.M.M. and A.P.H. (Ref 306173), and the Wellcome Trust core-funded Wellcome Centre for Investigative Parasitology (Ref 104111). C.S., J.P., and G.J.I. were supported by CRUK core funding to the CRUK Scotland Institute (A31287) and to G.J.I. (A29802). X-ray data were collected at Southeast Regional Collaborative Access Team (SER-CAT) 22-ID beamline at the Advanced Photon Source, Argonne National Laboratory. SER-CAT is supported by its member institutions, and equipment grants (RR25528, RR028976, and OD027000) from the NIH.
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https://pub.demo35.eprints-hosting.org/id/eprint/46
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Unnamed user with email ejo1f20@soton.ac.uk
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Date Deposited:
11 Jun 2025 16:34
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