Proteomics

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


ABSTRACT: The murine helminth parasite Heligmosomoides polygyrus expresses a family of modular proteins which, replicating the functional activity of the immunomodulatory cytokine TGF-β, have been named TGM (TGF-β Μimic). Multiple domains bind to different receptors, including TGF-β receptors TβRI (ALK5) and TβRII through domains 1-3, and prototypic family member TGM1 binds the cell surface co-receptor CD44 through domains 4-5. This allows TGM1 to induce T lymphocyte Foxp3 expression, characteristic of regulatory (Treg) cells, and to activate a range of TGF-β-responsive cell types. In contrast, a related protein, TGM4, targets a much more restricted cell repertoire, primarily acting on myeloid cells, with less potent effects on T cells and lacking activity on other TGF-β-responsive cell types. TGM4 binds avidly to myeloid cells by flow cytometry, and can outcompete TGM1 for cell binding. Analysis of receptor binding in comparison to TGM1 reveals a 10-fold higher affinity than TGM1 for TGFβR-I (TβRI), but a 100-fold lower affinity for TβRII through Domain 3. Consequently, TGM4 is more dependent on co-receptor binding; in addition to CD44, TGM4 also engages CD49d (Itga4) through Domains 1-3, as well as CD206 and Neuropilin-1 through Domains 4 and 5. TGM4 was found to effectively modulate macrophage populations, inhibiting lipopolysaccharide-driven inflammatory cytokine production and boosting interleukin (IL)-4-stimulated responses such as Arginase-1 in vitro and in vivo. These results reveal that the modular nature of TGMs has allowed the fine tuning of the binding affinities of the TβR- and co-receptor binding domains to establish cell specificity for TGF-β signalling in a manner that cannot be attained by the mammalian cytokine.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Spleen, Fibroblast, Macrophage

DISEASE(S): Parasitic Helminthiasis Infectious Disease

SUBMITTER: Sergio Lilla  

LAB HEAD: Sara Rossana

PROVIDER: PXD048278 | Pride | 2024-11-15

REPOSITORIES: Pride

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