Modulating tenascin-C functions by targeting the MAtrix REgulating MOtif, "MAREMO".
Fiche publication
Date publication
février 2022
Journal
Matrix biology : journal of the International Society for Matrix Biology
Auteurs
Membres identifiés du Cancéropôle Est :
Dr OREND Gertraud, Dr SALOME Nathalie
Tous les auteurs :
Loustau T, Abou-Faycal C, Erne W, Zur Wiesch PA, Ksouri A, Imhof T, Mörgelin M, Li C, Mathieu M, Salomé N, Crémel G, Dhaouadi S, Bouhaouala-Zahar B, Koch M, Orend G
Lien Pubmed
Résumé
The extracellular matrix molecule Tenascin-C (TNC) promotes cancer and chronic inflammation by multiple mechanisms. Recently, TNC was shown to promote an immune suppressive tumor microenvironment (TME) through binding soluble chemoattracting factors, thus retaining leukocytes in the stroma. TNC also binds to fibronectin (FN) and other molecules, raising the question of a potential common TNC binding mechanism. By sequence comparison of two TNC-interacting domains in FN, the fifth (FN5) and thirteenth (FN13) fibronectin type III domains we identified a MAtrix REgulating MOtif "MAREMO" or M-motif that is highly conserved amongst vertebrates. By sequence analysis, structural modeling and functional analysis we found also putative M-motifs in TNC itself. We showed by negative staining electron microscopic imaging that the M-motif in FN mediates interactions with FN as well as with TNC. We generated two M-motif mimetic peptides P5 and P13 resembling the M-motif in FN5 and FN13, respectively. By using structural information we modelled binding of these M-motif mimetics revealing a putative MAREMO binding site MBS in FN5 and TN3, respectively overlapping with the M-motif. We further demonstrated that the M-motif mimetic peptides blocked several functions of TNC, such as binding of TNC to FN, cell rounding on a mixed FN/TNC substratum, FN matrix expression and subsequent assembly, TNC-induced signaling and gene expression, TNC chemokine binding and dendritic cell retention, thus providing novel opportunities to inhibit TNC actions. Our results suggest that targeting the MAREMO/MBS interaction could be exploited for reducing inflammation and matrix functions in cancer and fibrosis.
Mots clés
CCL21, CXCL12, Matrisome, Matrix Regulating Motif MAREMO, TGFβ, TRAIL, cell adhesion, chemoretention, fibronectin, gene expression, immune suppression, matrix assembly, proteomics, signaling, structural modeling, tenascin-C
Référence
Matrix Biol. 2022 Feb 25;: