Smyth, D. J. et al. (2018) TGF-β mimic proteins form an extended gene family in the murine parasite Heligmosomoides polygyrus. International Journal for Parasitology, 48(5), pp. 379-385. (doi: 10.1016/j.ijpara.2017.12.004) (PMID:29510118) (PMCID:PMC5904571)
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Abstract
We recently reported the discovery of a new parasite-derived protein that functionally mimics the immunosuppressive cytokine transforming growth factor (TGF)-β. The Heligmosomoides polygyrus TGF-β Mimic (Hp-TGM) shares no homology to any TGF-β family member, however it binds the mammalian TGF-β receptor and induces expression of Foxp3, the canonical transcription factor of both mouse and human regulatory T cells. Hp-TGM consists of five atypical Complement Control Protein (CCP, Pfam 00084) domains, each lacking certain conserved residues and 12–15 amino acids longer than the 60–70 amino acids consensus domain, but with a recognizable 3-cysteine, tryptophan, cysteine motif. We now report on the identification of a family of nine related Hp-TGM homologues represented in the secreted proteome and transcriptome of H. polygyrus. Recombinant proteins from five of the nine new TGM members were tested for TGF-β activity, but only two were functionally active in an MFB-F11 reporter assay, and by the induction of T cell Foxp3 expression. Sequence comparisons reveal that proteins with functional activity are similar or identical to Hp-TGM across the first three CCP domains, but more variable in domains 4 and 5. Inactive proteins diverged in all domains, or lacked some domains entirely. Testing truncated versions of Hp-TGM confirmed that domains 1–3 are essential for full activity in vitro, while domains 4 and 5 are not required. Further studies will elucidate whether these latter domains fulfill other functions in promoting host immune regulation during infection and if the more divergent family members play other roles in immunomodulation.
| Item Type: | Articles |
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| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Smyth, Dr Danielle and Gregory, Dr William and White, Dr Madeleine and Maizels, Professor Rick |
| Authors: | Smyth, D. J., Harcus, Y., White, M. P.J., Gregory, W. F., Nahler, J., Stephens, I., Toke-Bjolgerud, E., Hewitson, J. P., Ivens, A., McSorley, H. J., and Maizels, R. M. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Infection & Immunity |
| Journal Name: | International Journal for Parasitology |
| Publisher: | Elsevier |
| ISSN: | 0020-7519 |
| ISSN (Online): | 1879-0135 |
| Published Online: | 03 March 2018 |
| Copyright Holders: | Copyright © 2018 The Authors |
| First Published: | First published in International Journal for Parasitology 48(5): 379-385 |
| Publisher Policy: | Reproduced under a Creative Commons License |
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