PT  - JOURNAL ARTICLE
AU  - Javier Milara
AU  - Beatriz Ballester
AU  - Paula Montero
AU  - Juan Escriva
AU  - Enrique Artigues
AU  - Manuel Alós
AU  - Alfonso Pastor-Clerigues
AU  - Esteban Morcillo
AU  - Julio Cortijo
TI  - MUC1 intracellular bioactivation mediates lung fibrosis
AID  - 10.1136/thoraxjnl-2018-212735
DP  - 2020 Feb 01
TA  - Thorax
PG  - 132--142
VI  - 75
IP  - 2
4099  - http://thorax.bmj.com/content/75/2/132.short
4100  - http://thorax.bmj.com/content/75/2/132.full
SO  - Thorax2020 Feb 01; 75
AB  - 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.