TGF-β mimic proteins form an extended gene family in the murine parasite Heligmosomoides polygyrus

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
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 > Institute of Infection Immunity and Inflammation
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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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
765221Helminths and the Immune System: Regulation, Regulators and ImmunityRichard MaizelsWellcome Trust (WELLCOTR)106122/A/14/ZIII - PARASITOLOGY
371799The Wellcome Centre for Molecular Parasitology ( Core Support )Andrew WatersWellcome Trust (WELLCOTR)104111/Z/14/Z & AIII - PARASITOLOGY