Acute cigarette smoke exposure impairs proteasome function in the lung

Rijt, Sabine van; Keller, Ilona; Gorcsan, John; Kohse, Kathrin; Yildirim, Ali Önder; Eickelberg, Oliver; Meiners, Silke

doi:10.1152/ajplung.00128.2012

Cited by 88 publications

(94 citation statements)

References 37 publications

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“…We therefore assessed the role of HDAC6 in protein aggregation and clearance after CS exposure. CS, a potent prooxidant agent, is known to alter protein homeostasis by causing the oxidative modification of proteins, the disruption of protein folding, as well as altered protein processing in the ER, leading to the formation of protein aggregates (7)(8)(9). Consequently, protein aggregates may be solubilized by protein chaperones and removed by proteosomal degradation, or organized in centralized aggresomes and removed by the autophagic pathway (50).…”

Section: Cs-induced Autophagic Processing Of Ubiquitinated Proteins Imentioning

confidence: 99%

“…The mechanisms underlying CS-induced epithelial cell injury and dysfunction remain unclear, but may include a protease/antiprotease imbalance, inflammation, oxidative stress, and programmed cell death (2)(3)(4). Recent studies have suggested additional pathway mechanisms involving altered protein homeostasis (proteostasis) (5,6), including ER stress, inhibition of the ubiquitin-proteasome system (7)(8)(9), and autophagy (10)(11)(12)(13), all of which potentially contribute to the pathogenesis of chronic lung diseases and emphysema (5).…”

Section: Introductionmentioning

confidence: 99%

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Histone deacetylase 6–mediated selective autophagy regulates COPD-associated cilia dysfunction

et al. 2013

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Chronic obstructive pulmonary disease (COPD) involves aberrant airway inflammatory responses to cigarette smoke (CS) that are associated with epithelial cell dysfunction, cilia shortening, and mucociliary clearance disruption. Exposure to CS reduced cilia length and induced autophagy in vivo and in differentiated mouse tracheal epithelial cells (MTECs). Autophagy-impaired (Becn1 +/-or Map1lc3B -/-) mice and MTECs resisted CS-induced cilia shortening. Furthermore, CS increased the autophagic turnover of ciliary proteins, indicating that autophagy may regulate cilia homeostasis. We identified cytosolic deacetylase HDAC6 as a critical regulator of autophagy-mediated cilia shortening during CS exposure. Mice bearing an X chromosome deletion of Hdac6 (Hdac6 -/Y ) and MTECs from these mice had reduced autophagy and were protected from CS-induced cilia shortening. Autophagy-impaired Becn1 -/-, Map1lc3B -/-, and Hdac6 -/Y mice or mice injected with an HDAC6 inhibitor were protected from CS-induced mucociliary clearance (MCC) disruption. MCC was preserved in mice given the chemical chaperone 4-phenylbutyric acid, but was disrupted in mice lacking the transcription factor NRF2, suggesting that oxidative stress and altered proteostasis contribute to the disruption of MCC. Analysis of human COPD specimens revealed epigenetic deregulation of HDAC6 by hypomethylation and increased protein expression in the airways. We conclude that an autophagy-dependent pathway regulates cilia length during CS exposure and has potential as a therapeutic target for COPD.

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Section: Cs-induced Autophagic Processing Of Ubiquitinated Proteins Imentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Histone deacetylase 6–mediated selective autophagy regulates COPD-associated cilia dysfunction

et al. 2013

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“…of cystic fibrosis transmembrane conductance regulator (CFTR), which may also contribute to COPD pathogenesis [70][71][72][73][74][75]. Of note, the proteasome itself is a direct target for environmental challenges as cigarette smoke and diesel exhaust have been shown to impair proteasome function [76,77]. In accordance with that observation, proteasome function is reduced in lungs of COPD patients and in mouse models of chronic cigarette exposure, which correlates inversely with the loss of lung function [79].…”

Section: Loss Of Proteostasismentioning

confidence: 95%

Hallmarks of the ageing lung

2015

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Ageing is the main risk factor for major non-communicable chronic lung diseases, including chronic obstructive pulmonary disease, most forms of lung cancer and idiopathic pulmonary fibrosis. While the prevalence of these diseases continually increases with age, their respective incidence peaks at different times during the lifespan, suggesting specific effects of ageing on the onset and/or pathogenesis of chronic obstructive pulmonary disease, lung cancer and idiopathic pulmonary fibrosis. Recently, the nine hallmarks of ageing have been defined as cell-autonomous and non-autonomous pathways involved in ageing. Here, we review the available evidence for the involvement of each of these hallmarks in the pathogenesis of chronic obstructive pulmonary disease, lung cancer, or idiopathic pulmonary fibrosis. Importantly, we propose an additional hallmark, "dysregulation of the extracellular matrix", which we argue acts as a crucial modifier of cell-autonomous changes and functions, and as a key feature of the above-mentioned lung diseases. @ERSpublications Hallmarks of ageing are selecting factors for the pathogenesis of COPD, lung cancer and IPF

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“…Hence, it is highly likely that CS and aging modulate a common process, such as proteostasis, that can affect multiple cellular pathways to promote COPD-emphysema pathogenesis (15). In fact, CS and age-related proteostasis imbalance are known to modulate proteasomal degradation (13,14,21,22), which can induce accumulation of ubiquitinated proteins as aggresome bodies. Aggresomes are insoluble clusters of ubiquitinated proteins that are formed as a cellular response mechanism to decreased proteasomal activity (23)(24)(25)(26)(27).…”

Section: Clinical Relevancementioning

confidence: 99%

Role of Cigarette Smoke–Induced Aggresome Formation in Chronic Obstructive Pulmonary Disease–Emphysema Pathogenesis

Tran

et al. 2015

Am J Respir Cell Mol Biol

121

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Cigarette smoke (CS) exposure is known to induce proteostasis imbalance that can initiate accumulation of ubiquitinated proteins. Therefore, the primary goal of this study was to determine if first-and secondhand CS induces localization of ubiquitinated proteins in perinuclear spaces as aggresome bodies. Furthermore, we sought to determine the mechanism by which smoke-induced aggresome formation contributes to chronic obstructive pulmonary disease (COPD)-emphysema pathogenesis. Hence, Beas2b cells were treated with CS extract (CSE) for in vitro experimental analysis of CSinduced aggresome formation by immunoblotting, microscopy, and reporter assays, whereas chronic CS-exposed murine model and human COPD-emphysema lung tissues were used for validation. In preliminary analysis, we observed a significant (P , 0.01) increase in ubiquitinated protein aggregation in the insoluble protein fraction of CSE-treated Beas2b cells. We verified that CS-induced ubiquitin aggregrates are localized in the perinuclear spaces as aggresome bodies. These CS-induced aggresomes (P , 0.001) colocalize with autophagy protein microtubule-associated protein 1 light chain-3B 1 autophagy bodies, whereas U.S. Food and Drug Administration-approved autophagy-inducing drug (carbamazepine) significantly (P , 0.01) decreases their colocalization and expression, suggesting CS-impaired autophagy. Moreover, CSE treatment significantly increases valosin-containing protein-p62 protein-protein interaction (P , 0.0005) and p62 expression (aberrant autophagy marker; P , 0.0001), verifying CSimpaired autophagy as an aggresome formation mechanism. We also found that inhibiting protein synthesis by cycloheximide does not deplete CS-induced ubiquitinated protein aggregates, suggesting the role of CS-induced protein synthesis in aggresome formation. Next, we used an emphysema murine model to verify that chronic CS significantly (P , 0.0005) induces aggresome formation. Moreover, we observed that autophagy induction by carbamazepine inhibits CS-induced aggresome formation and alveolar space enlargement (P , 0.001), confirming involvement of aggresome bodies in COPD-emphysema pathogenesis. Finally, significantly higher p62 accumulation in smokers and severe COPD-emphysema lungs (Global Initiative for Chronic Obstructive Lung Disease Stage III/IV) as compared with normal nonsmokers (Global Initiative for Chronic Obstructive Lung Disease Stage 0) substantiates the pathogenic role of autophagy impairment in aggresome formation and COPD-emphysema progression. In conclusion, CS-induced aggresome formation is a novel mechanism involved in COPD-emphysema pathogenesis.Keywords: cigarette smoke; chronic obstructive pulmonary disease; ubiquitin; aggresomes; autophagy Clinical RelevanceWe anticipate that these research findings will have a great impact on development of novel therapeutics for treatment of chronic obstructive pulmonary disease-emphysema and other diseases involving impaired proteostasis or autophagy. In addition to the therapeutic application, thes...

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Acute cigarette smoke exposure impairs proteasome function in the lung

Cited by 88 publications

References 37 publications

Histone deacetylase 6–mediated selective autophagy regulates COPD-associated cilia dysfunction

Histone deacetylase 6–mediated selective autophagy regulates COPD-associated cilia dysfunction

Hallmarks of the ageing lung

Role of Cigarette Smoke–Induced Aggresome Formation in Chronic Obstructive Pulmonary Disease–Emphysema Pathogenesis

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