Abstract

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 Thr455 and Ser490 and of TEAD4 at Ser69 and Ser99. 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.

Details

Title
O-GlcNAcylation controls pro-fibrotic transcriptional regulatory signaling in myofibroblasts
Author
Very, Ninon 1   VIAFID ORCID Logo  ; Boulet, Clémence 1 ; Gheeraert, Céline 1 ; Berthier, Alexandre 1 ; Johanns, Manuel 1 ; Bou Saleh, Mohamed 2 ; Guille, Loïc 1   VIAFID ORCID Logo  ; Bray, Fabrice 3 ; Strub, Jean-Marc 4   VIAFID ORCID Logo  ; Bobowski-Gerard, Marie 1   VIAFID ORCID Logo  ; Zummo, Francesco P. 1   VIAFID ORCID Logo  ; Vallez, Emmanuelle 1 ; Molendi-Coste, Olivier 1   VIAFID ORCID Logo  ; Woitrain, Eloise 1 ; Cianférani, Sarah 4 ; Montaigne, David 1 ; Ntandja-Wandji, Line Carolle 2 ; Dubuquoy, Laurent 2   VIAFID ORCID Logo  ; Dubois-Chevalier, Julie 1 ; Staels, Bart 1   VIAFID ORCID Logo  ; Lefebvre, Philippe 1 ; Eeckhoute, Jérôme 1   VIAFID ORCID Logo 

 U1011-EGID, Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, Lille, France (GRID:grid.503422.2) (ISNI:0000 0001 2242 6780) 
 U1286 - INFINITE – Institute for Translational Research in Inflammation, Univ. Lille, Inserm, CHU Lille, Lille, France (GRID:grid.523042.2) (ISNI:0000 0005 1242 5775) 
 University of Lille, Miniaturization for Synthesis, Analysis & Proteomics, UAR 3290, CNRS, Villeneuve d’Ascq Cedex, France (GRID:grid.503422.2) (ISNI:0000 0001 2242 6780) 
 Infrastructure Nationale de Protéomique ProFI - FR2048, Laboratoire de Spectrométrie de Masse BioOrganique, CNRS UMR7178, Univ. Strasbourg, IPHC, Strasbourg, France (GRID:grid.11843.3f) (ISNI:0000 0001 2157 9291) 
Pages
391
Publication year
2024
Publication date
Jun 2024
Publisher
Springer Nature B.V.
e-ISSN
20414889
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
3063931474
Copyright
© The Author(s) 2024. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.