The TGF-β mimic TGM4 achieves cell specificity through combinatorial surface co-receptor binding
The immunoregulatory cytokine TGF-β is pleiotropic due to the near-ubiquitous expression of the TGF-β receptors TβRI and TβRII on diverse cell types. The helminth parasite Heligmosomoides polygyrus has convergently evolved a family of TGF-β mimics (TGMs) that bind both these receptors through domains 1-3 of a 5-domain protein. One member of this family, TGM4, differs from TGF-β in acting in a cell-specific manner, failing to stimulate fibroblasts, but activating SMAD phosphorylation in macrophages. Primarily through domains 4 and 5, TGM4 interacts with multiple co-receptors, including CD44, CD49d (integrin α4) and CD206, and can up- and downmodulate macrophage responses to IL-4 and lipopolysaccharide (LPS), respectively. The dependence of TGM4 on combinatorial interactions with co-receptors is due to a moderated affinity for TβRII that is more than 100-fold lower than for TGF-β. Thus the parasite has elaborated TGF-β receptor interactions to establish cell specificity through combinatorial cis-signalling, an innovation absent from the mammalian cytokine.
Authors
- Cynthia S. Hinck (ORCID: https://orcid.org/0000-0002-2163-9378)
- Chang‐Hyeock Byeon (ORCID: https://orcid.org/0000-0001-9997-7708)
- Danielle J. Smyth (ORCID: https://orcid.org/0000-0001-6080-2679)
- 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)
- Sara Zanivan (ORCID: https://orcid.org/0000-0002-9880-9099)
- Claire Ciancia
- 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)
- Sérgio Lilla (ORCID: https://orcid.org/0000-0003-3142-7640)
- Anna Sanders (ORCID: https://orcid.org/0009-0004-5829-4942)
- Regina Jin (ORCID: https://orcid.org/0009-0004-2489-3074)
- Madeleine P. J. White (ORCID: https://orcid.org/0000-0002-0152-1110)
- Rosemary G. White (ORCID: https://orcid.org/0000-0002-7618-3814)
- Natalia Wąsowska
Institutions
- University of Pittsburgh (US)
- University of Dundee (GB)
- Leiden University Medical Center (NL)
- Cancer Research UK (GB)
- Gillies McIndoe Research Institute (NZ)
- Comprehensive Cancer Center Vienna (AT)
- Wellcome Centre for Molecular Parasitology (GB)
- Oncode Institute (NL)
- Birla Institute of Technology and Science, Pilani (IN)
- Medical University of Vienna (AT)
- University of Glasgow (GB)
Publication Details
- Journal
- EMBO Reports
- Published
- 2024-11-28
- DOI
- https://doi.org/10.1038/s44319-024-00323-2
- Citations
- 8
- Primary Topic
- Parasites and Host Interactions
- Type
- article
- Field-Weighted Citation Impact
- 4.12
Funders
- Wellcome Trust
- Cancer Research UK
- University of Glasgow
- Lung Foundation Netherlands
- Oncode Institute
- National Institutes of Health
- Beatson Institute for Cancer Research
- National Institute of Allergy and Infectious Diseases