What shall we do with the damaged proteins in lung disease? Ask the proteasome!

Meiners, Silke; Eickelberg, Oliver

doi:10.1183/09031936.00208511

Cited by 24 publications

(19 citation statements)

References 108 publications

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“…Expression of the ␣5 (outer ring)-, ␤1 (caspase-like activity)-, and ␤2 (trypsin-like activity)-subunits of the 20S core particle for smoked and nonsmoked mice lungs remained unaffected as shown by Western blot analysis (n ϭ 6/group). uitin-mediated proteasomal degradation (28). Accumulation of ubiquitinated proteins in acutely cigarette smoke-exposed mice has recently been shown by fluorescent microscopy (29).…”

Section: Discussionmentioning

confidence: 98%

Acute cigarette smoke exposure impairs proteasome function in the lung

Rijt

Keller

Gorcsan

et al. 2012

American Journal of Physiology-Lung Cellular and Molecular Phys

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Cigarette smoke mediates DNA damage, lipid peroxidation, and modification and misfolding of proteins, thereby inducing severe cellular damage. The ubiquitin proteasome system serves as the major disposal system for modified and misfolded proteins and is thus essential for proper cellular function. Its role in cigarette smoke-induced cell damage, however, is largely unknown. We hypothesized that the ubiquitin-proteasome system is involved in the degradation of cigarette smoke-damaged proteins and that cigarette smoke exposure impairs the proteasome itself. Here, we show that treatment of human alveolar epithelial cells with cigarette smoke extract (CSE) induced time- and dose-dependent cell death, a rise in intracellular reactive oxygen species, and increased levels of carbonylated and polyubiquitinated proteins. While high doses of CSE severely impaired all three proteasomal activities, low CSE concentrations significantly inhibited only the trypsin-like activity of the proteasome in alveolar and bronchial epithelial cells. Moreover, acute exposure of mice to cigarette smoke significantly impaired the trypsin-like activity by 25% in the lungs. Reduced proteasome activity was not due to transcriptional regulation of the proteasome. Notably, cigarette smoke exposure induced accumulation of polyubiquitinated proteins in the soluble and insoluble protein fraction of the lung. We show for the first time that acute exposure to cigarette smoke directly impairs proteasome activity in the lungs of mice and in human epithelial cells at low doses without affecting proteasome expression. Our results indicate that defective proteasomal protein quality control may exacerbate the detrimental effects of cigarette smoke in the lung.

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Section: Discussionmentioning

confidence: 98%

Acute cigarette smoke exposure impairs proteasome function in the lung

Rijt

Keller

Gorcsan

et al. 2012

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…In this model system, we found the applied CS doses to be nontoxic as assessed by the absence of apoptotic and necrotic cell death markers. Nontoxic doses of CS have been shown to affect function and activity of numerous cellular proteins and impair overall protein homeostasis in lung alveolar and bronchial cells (6,29,35). Furthermore, CS affects organelle-specific proteostasis as shown for activation of the unfolded protein response in the endoplasmic reticulum in lung tissue homogenates of chronic smokers and in CSEtreated cells (22,47).…”

Section: Discussionmentioning

confidence: 99%

Cigarette smoke extract affects mitochondrial function in alveolar epithelial cells

Ballweg

Mutze

Königshoff

et al. 2014

American Journal of Physiology-Lung Cellular and Molecular Phys

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Ballweg K, Mutze K, Königshoff M, Eickelberg O, Meiners S. Cigarette smoke extract affects mitochondrial function in alveolar epithelial cells. Am J Physiol Lung Cell Mol Physiol 307: L895-L907, 2014. First published October 17, 2014 doi:10.1152/ajplung.00180.2014.-Cigarette smoke is the main risk factor for chronic obstructive pulmonary disease (COPD). Exposure of cells to cigarette smoke induces an initial adaptive cellular stress response involving increased oxidative stress and induction of inflammatory signaling pathways. Exposure of mitochondria to cellular stress alters their fusion/fission dynamics. Whereas mild stress induces a prosurvival response termed stressinduced mitochondrial hyperfusion, severe stress results in mitochondrial fragmentation and mitophagy. In the present study, we analyzed the mitochondrial response to mild and nontoxic doses of cigarette smoke extract (CSE) in alveolar epithelial cells. We characterized mitochondrial morphology, expression of mitochondrial fusion and fission genes, markers of mitochondrial proteostasis, as well as mitochondrial functions such as membrane potential and oxygen consumption. Murine lung epithelial (MLE)12 and primary mouse alveolar epithelial cells revealed pronounced mitochondrial hyperfusion upon treatment with CSE, accompanied by increased expression of the mitochondrial fusion protein mitofusin 2 and increased metabolic activity. We did not observe any alterations in mitochondrial proteostasis, i.e., induction of the mitochondrial unfolded protein response or mitophagy. Therefore, our data indicate an adaptive prosurvival response of mitochondria of alveolar epithelial cells to nontoxic concentrations of CSE. A hyperfused mitochondrial network, however, renders the cell more vulnerable to additional stress, such as sustained cigarette smoke exposure. As such, cigarette smoke-induced mitochondrial hyperfusion, although part of a beneficial adaptive stress response in the first place, may contribute to the pathogenesis of COPD. chronic obstructive pulmonary disease; emphysema; proteostasis; stress-induced mitochondrial hyperfusion CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) is one of the leading causes of death worldwide. It is characterized by progressive and irreversible airflow limitation (4, 44). In the Western world, the main risk factor for development of COPD is cigarette smoke (CS) (4, 44), which is a complex mixture of thousands of injurious agents and reactive oxidants (7,33,44). Exposure of lung epithelial cells to CS initiates an adaptive cell response, such as induction of autophagy, impaired proteasome function, and proinflammatory and oxidative responses (7,33,35).Mitochondria are crucial cellular organelles for cellular energetics, signaling, and apoptosis. Differences in cellular energy demands or cellular stress rapidly alter mitochondrial behavior mainly by changing mitochondrial fusion and fission dynamics (5, 9, 26). Mitochondrial hyperfusion provides a stress-resolving mechanism for the cell, as elongated mitochondria are pr...

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“…Evidence indicates that ER stress can be induced by common pathogens to which the lungs are exposed, such as viral and bacterial infections, 4 environmental pollution, 5 chemical compounds, 6 and cigarette smoke (CS) 7 ( Fig 2 ). ER stress may also be triggered by a default in the molecules associated with the secretory pathway and in the ERAD pathway 8 or by the trapping of misfolded proteins in the ER as a result of the genetic mutations discussed later. Aging may also contribute to heightened ER stress because of a loss of chaperones and folding molecules localized in the ER.…”

Section: Er Stress In Lungsmentioning

confidence: 98%