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Mechanism of action of parasite TGFb antagonist via mouse (co-)receptors inspires creation of novel cell-type-specific TGFb modulators

ABSTRACT: A murine parasite modulates host responses by secreting modular TGFβ mimics (TGMs). Among these, the agonist TGM1 consists of five distinct domains (D); D1/2, D3, and D4/5 interact with the host (co-)receptors TGFBR1, TGFBR2, and CD44, respectively. In contrast, antagonist TGM6 lacks the D1/2 domains that bind to TGFBR1 but retains thed3-TGFBR2 interaction. First, we found that TGM6 antagonize TGFb/SMAD signaling on mice but not on human cells, with the amino acid differences in the extracellular domain of TGFBR2 being responsible for this disparity. Next, we demonstrated that TGM6 competes with TGFβ for its interaction with mouse TGFBR. Importantly, we identified using biochemical assays that betaglycan and low-density lipoprotein receptor-related protein 1 (LRP1) act as TGM6 co-receptors. The D4/5 domains of TGM6 interact with LRP1, while betaglycan requires TGFBR2 for effective binding to TGM6-D3. Through genetic misexpression and cell biological experiments, we showed that LRP1 is essential for cell-specific antagonism by TGM6, while betaglycan counteracts TGM6's function. The modular structure of TGMs enabled us to create chimeras of TGM1 and TGM6, thereby changing TGM6 cell-type specificity and converting the antagonist into an agonist.

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ORGANISM(S): Mus Musculus (mouse)

SUBMITTER: Román González-Prieto

LAB HEAD: Roman González-Prieto

PROVIDER: PXD065047 | Pride | 2026-04-15

REPOSITORIES: Pride

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Project description:Background: Supplementing farm animals diet with functional ingredients may improve the nutritional quality of meat products. Diet composition has been also demonstrated to influence the gene expression with effect on biological processes and pathways. However, the knowledge on the effect of nutrients at the molecular level is scant. In particular, studies on the effects of antioxidants and polyphenols dietary supplementation have been investigated mainly in rodents, and only scarcely in farm animals so far. RNA-seq with next-generation sequencing (NGS) is increasingly the method of choice for studying changes in the transcriptome and it has been recently employed also in pig nutrigenomics studies to identify diet-induced changes in gene expression. The present study aimed to investigate the effect of diets enriched with functional ingredients (linseed, vitamin E and plant extracts) on the transcriptome of pig Longissimus thoracis to elucidate the role of these compounds in influencing genes involved in muscle physiology and metabolism compared to a standard diet. Results: 893 significant differentially expressed genes (DEGs) (FDR adjusted P-value < 0.05) were detected by RNA-seq analysis in the three diet comparisons (D2-D1, D3-D1, D4-D1). The functional analysis of DEGs showed that the diet enriched with n-3 PUFA from linseed (D2) mostly downregulated genes, compared to the standard diet (D1) included in pathways and biological processes (BPs) involved in muscle development, contraction, and glycogen metabolism. The diet supplemented with linseed and vitamin E/Selenium (D3) compared to D1 mostly downregulated genes linked to oxidative phosphorylation. Only few genes were upregulated by the D3 and involved in extracellular matrix (ECM) organization. Finally, the comparison D4-D1 showed that the diet supplemented with linseed and plant extracts (D4) upregulated the majority of genes compared to D1 that were included in a complex network of pathways and BPs all connected by hub genes. In particular, IGF2 was a hub gene connecting protein metabolism, ECM organization, immune system and lipid biosynthesis pathways. Conclusion: The supplementation of pig diet with n-3 PUFA from linseed, antioxidants and plant-derived polyphenols can influence the expression of a relevant number of genes in Longissimus thoracis muscle that are involved a variety of biochemical pathways linked to muscle function and metabolism.

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Mechanism of action of parasite TGFb antagonist via mouse (co-)receptors inspires creation of novel cell-type-specific TGFb modulators

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