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Semren, N. ; Welk, V. ; Korfei, M.* ; Keller, I.E. ; Fernandez, I.E. ; Adler, H. ; Günther, A.* ; Eickelberg, O. ; Meiners, S.

Regulation of 26S proteasome activity in pulmonary fibrosis.

Am. J. Respir. Crit. Care Med. 192, 1089-1101 (2015)
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RATIONALE: The ubiquitin-proteasome system is critical for maintenance of protein homeostasis by degrading polyubiquitinated proteins in a spatially and timely controlled manner. Cell and protein homeostasis are altered upon pathological tissue remodelling. 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 remodelling, thereby contributing to the pathogenesis of idiopathic pulmonary fibrosis (IPF). METHODS: To investigate proteasome function during myofibroblast differentiation, we treated lung fibroblasts with TGF-β and examined proteasome composition and activity. For in vivo analysis, we used mouse models of lung fibrosis and fibrotic human lung tissue. MEASUREMENTS AND MAIN 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 was detected during bleomycin-induced lung remodelling and fibrosis. Importantly, Rpn6 is overexpressed in myofibroblasts and basal cells of the brochiolar epithelium in lungs of patients with IPF, which is accompanied by enhanced protein polyubiquitination. CONCLUSION: Our study identifies Rpn6-dependent 26S proteasome activation as an essential feature of myofibroblast differentiation in vitro and in vivo and suggests an important role in IPF pathogenesis.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Ipf ; Myofibroblast Differentiation ; Proteasome
ISSN (print) / ISBN 1073-449X
e-ISSN 1535-4970
Zeitschrift American Journal of Respiratory and Critical Care Medicine
Quellenangaben Band: 192, Heft: 9, Seiten: 1089-1101 Artikelnummer: , Supplement: ,
Verlag American Thoracic Society
Begutachtungsstatus