PT  - JOURNAL ARTICLE
AU  - Nora Semren
AU  - Martina Korfei
AU  - Isis Fernandez
AU  - Andreas Günther
AU  - Oliver Eickelberg
AU  - Silke Meiners
TI  - Proteasome function in pulmonary fibrosis
DP  - 2014 Sep 01
TA  - European Respiratory Journal
PG  - 1421
VI  - 44
IP  - Suppl 58
4099  - http://erj.ersjournals.com/content/44/Suppl_58/1421.short
4100  - http://erj.ersjournals.com/content/44/Suppl_58/1421.full
SO  - Eur Respir J2014 Sep 01; 44
AB  - Pathological remodeling processes in IPF critically depend on a proper function of protein homeostasis in lung cells. The proteasome, a multicatalytic protease, is crucial for maintainance of protein homeostasis. It consists of a catalytic core (20S) and a regulator (19S), together forming highly active 26S proteasomes.Here, we examined the role of the proteasome in myofibroblast differentiation and its dysregulation in the pathogenesis of lung fibrosis.CCL206 lung fibroblasts were treated with TGF-β1 to induce myofibroblast differentiation and proteasome activity was assayed by specific luminescent substrates and native gel analysis. Proteasome activity was significantly increased in TGF-β1-treated cells, while expression of 20S subunits remained unchanged. Further, 26S formation was elevated and accompanied by higher protein expression of the 19S subunit Rpn6 which serves as a key regulator for the assembly of 26S proteasomes. siRNA-mediated silencing of Rpn6 counteracted 26S formation, decreased proteasome activity and also impaired proliferation of TGF-β1 treated fibroblasts. In primary human lung fibroblasts silencing of Rpn6 induced G1 cell cycle arrest and reduced collagen-1 expression. 26S proteasome activities were also increased in fibrotic lungs of bleomycin-treated mice. Immunohistochemistry of IPF lungs showed strong staining for Rpn6 in myofibroblasts and an increase in K48-polyubiquitinated proteins indicating an elevated protein turnover in these cells.Myofibroblast differentiation is associated with increased proteasome activity involving enhanced formation of active 26S proteasome complexes via the proteasomal subunit Rpn6. This suggests an important contribution of the proteasome for profibrotic cellular remodeling.