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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)
Postprint DOI PMC
Open Access Green
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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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Ipf ; Myofibroblast Differentiation ; Proteasome
ISSN (print) / ISBN 1073-449X
e-ISSN 1535-4970
Journal American Journal of Respiratory and Critical Care Medicine
Quellenangaben Volume: 192, Issue: 9, Pages: 1089-1101 Article Number: , Supplement: ,
Publisher American Thoracic Society
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Lung Health and Immunity (LHI)
Research Unit Gene Vector (AGV)