title: Regulation of 26S Proteasome Activity in Pulmonary Fibrosis.
abstract: BACKGROUND
  The ubiquitin-proteasome system is critical for maintenance of protein homeostasis by degrading polyubiquitinated proteins in a spatially and temporally controlled manner. Cell and protein homeostasis are altered upon pathological tissue remodeling. Dysregulation of the proteasome has been reported for several chronic diseases of the heart, brain, and lung. We hypothesized that proteasome function is altered upon fibrotic lung remodeling, thereby contributing to the pathogenesis of idiopathic pulmonary fibrosis (IPF).
  
  
  OBJECTIVE
  To investigate proteasome function during myofibroblast differentiation.
  
  
  METHODS
  We treated lung fibroblasts with transforming growth factor (TGF)-β and examined proteasome composition and activity. For in vivo analysis, we used mouse models of lung fibrosis and fibrotic human lung tissue.
  
  
  RESULTS
  We demonstrate that induction of myofibroblast differentiation by TGF-β involves activation of the 26S proteasome, which is critically dependent on the regulatory subunit Rpn6. Silencing of Rpn6 in primary human lung fibroblasts counteracted TGF-β-induced myofibroblast differentiation. Activation of the 26S proteasome and increased expression of Rpn6 were detected during bleomycin-induced lung remodeling and fibrosis. Importantly, Rpn6 is overexpressed in myofibroblasts and basal cells of the bronchiolar epithelium in lungs of patients with IPF, which is accompanied by enhanced protein polyubiquitination.
  
  
  CONCLUSIONS
  We identified Rpn6-dependent 26S proteasome activation as an essential feature of myofibroblast differentiation in vitro and in vivo, and our results suggest it has an important role in IPF pathogenesis.
authors.affiliation: 1 Comprehensive Pneumology Center (CPC), University Hospital of the Ludwig-Maximilians University (LMU), LMU, Helmholtz Zentrum München, Member of the German Center for Lung Research (DZL), Munich, Germany.
authors.forename: Nora
authors.initials: N
authors.lastname: Semren
authors.affiliation: 1 Comprehensive Pneumology Center (CPC), University Hospital of the Ludwig-Maximilians University (LMU), LMU, Helmholtz Zentrum München, Member of the German Center for Lung Research (DZL), Munich, Germany.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Welk
authors.affiliation: 2 Department of Internal Medicine, Universities of Giessen and Marburg Lung Center (UGMLC), Justus-Liebig-University Giessen, Member of the DZL, Giessen, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Korfei
authors.affiliation: 1 Comprehensive Pneumology Center (CPC), University Hospital of the Ludwig-Maximilians University (LMU), LMU, Helmholtz Zentrum München, Member of the German Center for Lung Research (DZL), Munich, Germany.
authors.forename: Ilona E
authors.initials: IE
authors.lastname: Keller
authors.affiliation: 1 Comprehensive Pneumology Center (CPC), University Hospital of the Ludwig-Maximilians University (LMU), LMU, Helmholtz Zentrum München, Member of the German Center for Lung Research (DZL), Munich, Germany.
authors.forename: Isis E
authors.initials: IE
authors.lastname: Fernandez
authors.affiliation: 3 Research Unit Gene Vectors, Helmholtz Zentrum München, Munich, Germany.
authors.forename: Heiko
authors.initials: H
authors.lastname: Adler
authors.affiliation: 2 Department of Internal Medicine, Universities of Giessen and Marburg Lung Center (UGMLC), Justus-Liebig-University Giessen, Member of the DZL, Giessen, Germany.|4 Agaplesion Lung Clinic Waldhof Elgershausen, Greifenstein, Germany; and.|5 European IPF Network and European IPF Registry, Giessen, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Günther
authors.affiliation: 1 Comprehensive Pneumology Center (CPC), University Hospital of the Ludwig-Maximilians University (LMU), LMU, Helmholtz Zentrum München, Member of the German Center for Lung Research (DZL), Munich, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Eickelberg
authors.affiliation: 1 Comprehensive Pneumology Center (CPC), University Hospital of the Ludwig-Maximilians University (LMU), LMU, Helmholtz Zentrum München, Member of the German Center for Lung Research (DZL), Munich, Germany.
authors.forename: Silke
authors.initials: S
authors.lastname: Meiners
mesh_terms: D000818:Animals; D015153:Blotting, Western; D018929:Cell Culture Techniques; D002454:Cell Differentiation / Q000502:physiology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000378:metabolism* / Q000503:physiopathology*; D008168:Lung / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D008875:Middle Aged; D058628:Myofibroblasts / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease
keywords: idiopathic pulmonary fibrosis; myofibroblast differentiation; proteasome