Background Serum KL6/mucin 1 (MUC1) has been identified as a potential biomarker in idiopathic pulmonary fibrosis (IPF), but the role of MUC1 intracellular bioactivation in IPF is unknown.
Objective To characterise MUC1 intracellular bioactivation in IPF.
Methods and results The expression and phosphorylation of Thr41 and Tyr46 on the intracellular MUC1-cytoplasmic tail (CT) was increased in patients with IPF (n=22) compared with healthy subjects (n=21) and localised to fibroblasts and hyperplastic alveolar type II cells. Transforming growth factor (TGF)-β1 phosphorylated SMAD3 and thereby increased the phosphorylation of MUC1-CT Thr41 and Tyr46 in lung fibroblasts and alveolar type II cells, activating β-catenin to form a phospho-Smad3/MUC1-CT and MUC1-CT/β-catenin nuclear complex. This nuclear complex promoted alveolar epithelial type II and fibroblast to myofibroblast transitions, as well as cell senescence and fibroblast proliferation. The inhibition of MUC1-CT nuclear translocation using the inhibitor, GO-201 or silencing MUC1 by siRNA, reduced myofibroblast transition, senescence and proliferation in vitro. Bleomycin-induced lung fibrosis was reduced in mice treated with GO-201 and in MUC1-knockout mice. The profibrotic lectin, galectin-3, directly activated MUC1-CT and served as a bridge between the TGF-β receptor and the MUC1-C domain, indicating TGF-β1-dependent and TGF-β1-independent intracellular bioactivation of MUC1.
Conclusions MUC1 intracellular bioactivation is enhanced in IPF and promotes fibrotic processes that could represent potential druggable targets for IPF.
- idiopathic pulmonary fibrosis
- interstitial fibrosis
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JM and BB contributed equally.
Contributors JM, BB, PM, AP-C, EM and JC designed and performed experiments and data analysis. JM, BB, JE, MA, EA and JC designed experiments and oversaw all data analysis. JM, BB, EM, JE, MA, EA and JC drafted the manuscript. All authors have critically revised the manuscript. All authors have read, reviewed and approved the final manuscript as submitted to take public responsibility for it.
Funding This work was supported by the grants SAF2017-82913-R (JC), FIS PI17/02158 (JM), JR18/00050 (JM), Fondo Europeo de desarrollo Regional (FEDER), RTI2018-096827-B-I00 (EM), CIBERES (CB06/06/0027), TRACE (TRA2009-0311), CM16/0022 (AP-C) of the Spanish Government and by research grants from the Regional Government Prometeo 2017/023/UV (JC, EM), ACIF/2016/341 (BB) from 'Generalitat Valenciana'.
Competing interests None declared.
Patient consent for publication Obtained.
Ethics approval The protocol was approved by the local research and independent ethics committee of the University General Consortium Hospital of Valencia, Spain (CEI CHGUV/052016).
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information.