The TGF-β mimic TGM4 achieves cell specificity through combinatorial surface co-receptor binding

EMBO Reports, vol. 26, pp. 218–244

Abstract

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 19

1. Shashi Prakash Singh

   Birla Institute of Technology and Science, Pilani · University of Glasgow

   Affiliation as printed

   Centre for Parasitology, School of Infection and Immunity, University of Glasgow, Glasgow, G12 8TA, UK

   Department of Biological Sciences, Birla Institute of Technology and Science, Pilani, Rajasthan, 333031, India

2. Danielle J. Smyth

   University of Dundee · University of Glasgow

   Affiliation as printed

   Centre for Parasitology, School of Infection and Immunity, University of Glasgow, Glasgow, G12 8TA, UK

   Division of Cell Signalling and Immunology, University of Dundee, Dundee, UK

3. Kyle T. Cunningham

   University of Glasgow

   Affiliation as printed

   Centre for Parasitology, School of Infection and Immunity, University of Glasgow, Glasgow, G12 8TA, UK

4. Ananya Mukundan

   University of Pittsburgh

   Affiliation as printed

   Department of Structural Biology, University of Pittsburgh, Pittsburgh, PA, USA

5. Chang‐Hyeock Byeon

   University of Pittsburgh

   Affiliation as printed

   Department of Structural Biology, University of Pittsburgh, Pittsburgh, PA, USA

6. Cynthia S. Hinck

   University of Pittsburgh

   Affiliation as printed

   Department of Structural Biology, University of Pittsburgh, Pittsburgh, PA, USA

7. Madeleine P. J. White

   Gillies McIndoe Research Institute · University of Glasgow

   Affiliation as printed

   Centre for Parasitology, School of Infection and Immunity, University of Glasgow, Glasgow, G12 8TA, UK

   Gillies McIndoe Research Institute, Wellington, New Zealand

8. Claire Ciancia

   University of Glasgow

   Affiliation as printed

   Centre for Parasitology, School of Infection and Immunity, University of Glasgow, Glasgow, G12 8TA, UK

9. Natalia Wąsowska Aachen

   Leiden University Medical Center · University of Glasgow

   Affiliation as printed

   Centre for Parasitology, School of Infection and Immunity, University of Glasgow, Glasgow, G12 8TA, UK

   Leiden University Medical Center, Leiden, The Netherlands

10. Anneke Sanders

    University of Glasgow

    Affiliation as printed

    Centre for Parasitology, School of Infection and Immunity, University of Glasgow, Glasgow, G12 8TA, UK

11. Regina Jin

    Medical University of Vienna · University of Glasgow

    Affiliation as printed

    Center for Cancer Research, Medical University of Vienna, Vienna, Austria

    Centre for Parasitology, School of Infection and Immunity, University of Glasgow, Glasgow, G12 8TA, UK

12. Sérgio Lilla

    Cancer Research UK Scotland Institute

    Affiliation as printed

    Cancer Research UK Scotland Institute, Glasgow, G61 1BD, UK

13. Sara R. Zanivan

    Cancer Research UK Scotland Institute · University of Glasgow

    Affiliation as printed

    Cancer Research UK Scotland Institute, Glasgow, G61 1BD, UK

    School of Cancer Sciences, University of Glasgow, Glasgow, UK

14. Christina Schoenherr

    Cancer Research UK Scotland Institute

    Affiliation as printed

    Cancer Research UK Scotland Institute, Glasgow, G61 1BD, UK

15. Gareth J. Inman

    Cancer Research UK Scotland Institute · University of Glasgow

    Affiliation as printed

    Cancer Research UK Scotland Institute, Glasgow, G61 1BD, UK

    School of Cancer Sciences, University of Glasgow, Glasgow, UK

16. Maarten van Dinther Aachen Oncode Institute Department of Cell and Chemical Biology

    Leiden University · Oncode Institute

    Affiliation as printed

    Oncode Institute and Department of Cell and Chemical Biology, University of Leiden, Leiden, The Netherlands

17. Peter ten Dijke Aachen Oncode Institute Department of Cell and Chemical Biology

    Leiden University · Oncode Institute

    Affiliation as printed

    Oncode Institute and Department of Cell and Chemical Biology, University of Leiden, Leiden, The Netherlands

18. Andrew P. Hinck

    University of Pittsburgh

    Affiliation as printed

    Department of Structural Biology, University of Pittsburgh, Pittsburgh, PA, USA

19. Rick M. Maizels corresponding

    Birla Institute of Technology and Science, Pilani · University of Glasgow

    Affiliation as printed

    Centre for Parasitology, School of Infection and Immunity, University of Glasgow, Glasgow, G12 8TA, UK. rick.maizels@glasgow.ac.uk

    Department of Biological Sciences, Birla Institute of Technology and Science, Pilani, Rajasthan, 333031, India. rick.maizels@glasgow.ac.uk