Abstract
The proteasome is essential for the selective degradation of most cellular proteins and is fine-tuned according to cellular needs. Proteasome activators serve as building blocks to adjust protein turnover in cell growth and differentiation. Understanding the cellular function of proteasome activation in more detail offers a new strategy for therapeutic targeting of proteasomal protein breakdown in disease. The role of the proteasome activator PA200 in cell function and its regulation in disease is unknown. In this study, we investigated the function of PA200 in myofibroblast differentiation and fibrotic tissue remodeling. PA200 was upregulated in hyperplastic basal cells and myofibroblasts of fibrotic lungs from patients with idiopathic pulmonary fibrosis. Increased expression of PA200 and enhanced formation of PA200-proteasome complexes was also evident in experimental fibrosis of the lung and kidney in vivo and in activated primary human myofibroblasts of the lung in vitro. Transient silencing and overexpression revealed that PA200 functions as a negative regulator of myofibroblast differentiation of human but not mouse cells. Our data thus suggest an unexpected and important role for PA200 in adjusting myofibroblast activation in response to pro-fibrotic stimuli, which fails in idiopathic pulmonary fibrosis.
Highlights
The proteasome is essential for the selective degradation of most cellular proteins and is fine-tuned according to cellular needs
We observed enhanced formation of alternative PA200-proteasome complexes in fibrotic tissue remodeling of lung and kidney and localized increased PA200 expression to hyperplastic basal cells and myofibroblasts in human Idiopathic pulmonary fibrosis (IPF) tissues. In accordance with this observation, PA200 expression was higher in undifferentiated basal cells compared to in vitro-differentiated bronchial epithelial cells and PA200-proteasome complexes were upregulated upon transforming growth factor (TGF)-β1-induced myofibroblast differentiation
PA200 acted as a negative regulator of myofibroblast differentiation and partly independent of TGF-β1
Summary
The proteasome is essential for the selective degradation of most cellular proteins and is fine-tuned according to cellular needs. The role of the proteasome activator PA200 in cell function and its regulation in disease is unknown. Proteasomes are intracellular protease complexes involved in the degradation of most cellular proteins, including unwanted, misfolded and aged proteins They function as essential regulators of cellular growth and differentiation[4]. Alternative proteasome activators function in an ATP- and ubiquitin-independent manner, their exact function, is Helmholtz Zentrum München, Member of the German Center for Lung Research (DZL), Max-Lebsche Platz 31, 81377, Munich, Germany. The proteasome activator PA200 is a 200 kDa, monomeric protein expressed in both the cytosolic and nuclear compartment It is composed of HEAT repeats forming a dome-like cap that binds to the 20S core particle and attaches to 26S proteasome complexes forming so-called hybrid proteasomes[12,13,14]. The present study focuses on the role of PA200 in myofibroblast differentiation and fibrotic tissue remodeling
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