Redirecting TGF-β signalling, inspired by adaptive evolution of parasite mimics.

The Transforming Growth Factor-β (TGF-β) pathway, which arose in early non- bilaterian metazoans, is essential for development and maintenance of tissues and for promoting pro-tolergenic signalling and immune homeostasis. However, dysregulation of this pathway underlies a wide range of human diseases, including cancer and tissue fibrosis. Owing to its ubiquitous role and its diverse modes of action, targeting TGF-β signaling often leads to adverse off- target effects. Here, we propose an evolutionary approach to address this crucial issue by harnessing, at the molecular level, the natural defence mechanisms of the helminth Heligmosomoides polygyrus. This parasite secretes modular TGF-β mimics (TGMs) that bind mammalian TGF-β receptors together with diverse cell surface co-receptors: TGM1 and TGM4 bind to CD44 on haematopoietic cells, TGM6 to LRP1 on fibroblasts, and TGM7 to gp130 on hepatocytes. TGM1 and TGM4 promote immune regulatory cells, while TGM6, lacking the module binding TGF-βRI, can block signalling, but only in cells expressing LRP-1. Different TGMs can thereby agonise or antagonise TGF-βR signalling in a context-dependent manner that the host cytokine cannot achieve. This remarkable evolutionary adaptation by the helminth provides a template to investigate and design new structures with novel functions with high potential for modulating TGF-β signalling in human diseases.