%A Aubert,Alexandre %A Mercier-Gouy,Perrine %A Aguero,Stéphanie %A Berthier,Laurent %A Liot,Sophie %A Prigent,Laura %A Alcaraz,Lindsay B. %A Verrier,Bernard %A Terreux,Raphaël %A Moali,Catherine %A Lambert,Elise %A Valcourt,Ulrich %D 2021 %J Frontiers in Immunology %C %F %G English %K Tenascins,Transforming Growth Factor (TGF)-b,Latent TGF-b activation,tissue homeostasis,Tumor Microenvironment,Immune cell modulation %Q %R 10.3389/fimmu.2021.613438 %W %L %M %P %7 %8 2021-May-13 %9 Original Research %+ Ulrich Valcourt,Laboratoire de Biologie Tissulaire et Ingénierie Thérapeutique (LBTI), UMR CNRS 5305, Université Lyon 1, Institut de Biologie et Chimie des Protéines,France,ulrich.valcourt@ibcp.fr %# %! Tenascins activate latent TGF-β %* %< %T Latent TGF-β Activation Is a Hallmark of the Tenascin Family %U https://www.frontiersin.org/articles/10.3389/fimmu.2021.613438 %V 12 %0 JOURNAL ARTICLE %@ 1664-3224 %X Transforming growth factor-β (TGF-β) isoforms are secreted as inactive complexes formed through non-covalent interactions between bioactive TGF-β entities and their N-terminal pro-domains called latency-associated peptides (LAP). Extracellular activation of latent TGF-β within this complex is a crucial step in the regulation of TGF-β activity for tissue homeostasis and immune cell function. We previously showed that the matrix glycoprotein Tenascin-X (TN-X) interacted with the small latent TGF-β complex and triggered the activation of the latent cytokine into a bioactive TGF-β. This activation most likely occurs through a conformational change within the latent TGF-β complex and requires the C-terminal fibrinogen-like (FBG) domain of the glycoprotein. As the FBG-like domain is highly conserved among the Tenascin family members, we hypothesized that Tenascin-C (TN-C), Tenascin-R (TN-R) and Tenascin-W (TN-W) might share with TN-X the ability to regulate TGF-β bioavailability through their C-terminal domain. Here, we demonstrate that purified recombinant full-length Tenascins associate with the small latent TGF-β complex through their FBG-like domains. This association promotes activation of the latent cytokine and subsequent TGF-β cell responses in mammary epithelial cells, such as cytostasis and epithelial-to-mesenchymal transition (EMT). Considering the pleiotropic role of TGF-β in numerous physiological and pathological contexts, our data indicate a novel common function for the Tenascin family in the regulation of tissue homeostasis under healthy and pathological conditions.