Journal article

Publication year: 2015

Pages: 1089-1101

Journal: American Journal of Respiratory and Critical Care Medicine

Volume number: 192

Issue number: 9

ISSN: 1073-449X

eISSN: 1535-4970

DOI Link: https://doi.org/10.1164/rccm.201412-2270OC

Publisher: American Thoracic Society

Abstract: 

Rationale: 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).

Objectives: To investigate proteasome function during myofibroblast differentiation.

Methods: We treated lung fibroblasts with transforming growth factor (TGF)-beta 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-beta 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-beta-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.

Harvard Citation style: Semren, N., Welk, V., Korfei, M., Keller, I., Fernandez, I., Adler, H., et al. (2015) Regulation of 26S Proteasome Activity in Pulmonary Fibrosis, American Journal of Respiratory and Critical Care Medicine, 192(9), pp. 1089-1101. https://doi.org/10.1164/rccm.201412-2270OC

APA Citation style: Semren, N., Welk, V., Korfei, M., Keller, I., Fernandez, I., Adler, H., Guenther, A., Eickelberg, O., & Meiners, S. (2015). Regulation of 26S Proteasome Activity in Pulmonary Fibrosis. American Journal of Respiratory and Critical Care Medicine. 192(9), 1089-1101. https://doi.org/10.1164/rccm.201412-2270OC