Fiche publication
Date publication
juin 2024
Journal
Cell death & disease
Auteurs
Membres identifiés du Cancéropôle Est :
Dr CIANFERANI Sarah
Tous les auteurs :
Very N, Boulet C, Gheeraert C, Berthier A, Johanns M, Bou Saleh M, Guille L, Bray F, Strub JM, Bobowski-Gerard M, Zummo FP, Vallez E, Molendi-Coste O, Woitrain E, Cianférani S, Montaigne D, Ntandja-Wandji LC, Dubuquoy L, Dubois-Chevalier J, Staels B, Lefebvre P, Eeckhoute J
Lien Pubmed
Résumé
Tissue injury causes activation of mesenchymal lineage cells into wound-repairing myofibroblasts (MFs), whose uncontrolled activity ultimately leads to fibrosis. Although this process is triggered by deep metabolic and transcriptional reprogramming, functional links between these two key events are not yet understood. Here, we report that the metabolic sensor post-translational modification O-linked β-D-N-acetylglucosaminylation (O-GlcNAcylation) is increased and required for myofibroblastic activation. Inhibition of protein O-GlcNAcylation impairs archetypal myofibloblast cellular activities including extracellular matrix gene expression and collagen secretion/deposition as defined in vitro and using ex vivo and in vivo murine liver injury models. Mechanistically, a multi-omics approach combining proteomic, epigenomic, and transcriptomic data mining revealed that O-GlcNAcylation controls the MF transcriptional program by targeting the transcription factors Basonuclin 2 (BNC2) and TEA domain transcription factor 4 (TEAD4) together with the Yes-associated protein 1 (YAP1) co-activator. Indeed, inhibition of protein O-GlcNAcylation impedes their stability leading to decreased functionality of the BNC2/TEAD4/YAP1 complex towards promoting activation of the MF transcriptional regulatory landscape. We found that this involves O-GlcNAcylation of BNC2 at Thr and Ser and of TEAD4 at Ser and Ser. Altogether, this study unravels protein O-GlcNAcylation as a key determinant of myofibroblastic activation and identifies its inhibition as an avenue to intervene with fibrogenic processes.
Mots clés
Myofibroblasts, metabolism, Animals, Mice, Signal Transduction, Humans, Fibrosis, metabolism, Transcription Factors, metabolism, YAP-Signaling Proteins, metabolism, Mice, Inbred C57BL, TEA Domain Transcription Factors, metabolism, Male, Protein Processing, Post-Translational, Acetylglucosamine, metabolism, Transcription, Genetic, Adaptor Proteins, Signal Transducing, metabolism
Référence
Cell Death Dis. 2024 06 3;15(6):391
