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Kadri, S. ; Mattner, L. ; Zeng, Z. ; Prakki, S.R.S. ; Verma, A.K. ; Cetin, U. ; Mayr, C.H. ; Ansari, M. ; Wei, X. ; Asgharpour, S. ; Wasik, A. ; Kneidinger, N.* ; Stoleriu, M.* ; Behr, J.* ; Polleux, J.* ; Yildirim, A.Ö. ; Sadeleer, L.J.D.* ; Wuyts, W.* ; Burgstaller, G. ; Mann, M.* ; Mück-Häusl, M. ; Schiller, H.B.

Mechanosensitive phosphorylation of NFATC4 at S213/S217 drives fibroblast-to-myofibroblast transition and fibrosis.

J. Clin. Invest. 136:e195121 (2026)
Publ. Version/Full Text Research data DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
Mechanosensitive feedback between tissue stiffness and cellular contractile forces instructs cell identity. To characterize phosphorylation-mediated mechanosensing, we charted the global phosphoproteome dynamics of primary human lung fibroblasts on fibronectin-coated polydimethylsiloxane substrates of defined stiffness. We identified a key signaling threshold at 2-8 kPa, above which cells activated cytoskeletal remodeling, ECM secretion, and transition to a CTHRC1+/ACTA2+ myofibroblast state, accompanied by stiffness-dependent phosphorylation of the transcription factor NFATC4 at S213/S217. In micro-CT staged pulmonary fibrosis tissues, NFATC4 expression increased progressively, colocalizing with CTHRC1 and ACTA2 in myofibroblasts. Transcription factor regulon inference from a multicohort pulmonary fibrosis atlas confirmed elevated NFATC4 activity in disease fibroblasts, revealing a core 119-gene NFATC4-dependent fibrotic program with CTHRC1 as a top target. Phosphomimetic S213D/S217D mutants drove myofibroblast differentiation on soft substrates independently of TGFB, while phospho-dead S213A/S217A mutants blocked differentiation even on stiff matrix with TGFB, establishing the phospho-switch as both necessary and sufficient. Stiff matrix and TGFB converged on this JNK- and calcineurin-dependent switch to amplify the fibrotic response. This positions NFATC4 S213/S217 as a mechanosensitive checkpoint for CTHRC1+ myofibroblast fate and a candidate therapeutic target in multiorgan fibrosis.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Mechanosensitive Channels ; Myofibroblast ; Transcription Factor ; Phosphorylation ; Fibrosis ; Mechanotransduction ; Pulmonary Fibrosis ; Extracellular Matrix ; Signal Transduction ; Transforming Growth Factor Beta
ISSN (print) / ISBN 0021-9738
e-ISSN 1558-8238
Journal Journal of Clinical Investigation
Quellenangaben Volume: 136, Issue: 17, Pages: , Article Number: e195121 Supplement: ,
Publisher American Society of Clinical Investigation
Reviewing status Peer reviewed
Institute(s) Research Unit Precision Regenerative Medicine (PRM)
Institute of Lung Health and Immunity (LHI)
Institute of Computational Biology (ICB)