Conditional deletion of Nedd4-2 in lung epithelial cells causes progressive pulmonary fibrosis in adult mice

Duerr, Julia; Leitz, Dominik; Szczygieł, Magdalena; Dvornikov, Dmytro; Fraumann, Simon G.; Kreutz, Clemens; Zadora, Piotr K.; Agircan, Ayça Seyhan; Konietzke, Philip; Engelmann, Theresa A.; Hegermann, Jan; Mulugeta, Surafel; Kawabe, Hiroshi; Knudsen, Lars; Ochs, Matthias; Rotin, Daniela; Muley, Thomas; Kreuter, Michael; Herth, Felix J.F.; Wielpütz, Mark O.; Beers, Michael F.; Klingmüller, Ursula; Mall, Marcus

doi:10.1038/s41467-020-15743-6

Cited by 56 publications

(95 citation statements)

References 95 publications

(137 reference statements)

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“…Impairing MCC would also be of benefit to fungal species trying to colonise the airway, giving an evolutionary advantage to those that induce MUC5AC expression. Future studies providing a clearer understanding of how proteases regulate the expression of MUC5B will be important not only in muco-obstructive lung disease, due to its role in MCC [ 58 ], but also the wider field of CLD including in idiopathic pulmonary fibrosis where a MUC5B promoter polymorphism and impaired MCC are associated with disease development [ 72 , 73 ].…”

Section: Proteases and Mucusmentioning

confidence: 99%

Proteases, Mucus, and Mucosal Immunity in Chronic Lung Disease

McKelvey

Brown

Ryan

et al. 2021

IJMS

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Dysregulated protease activity has long been implicated in the pathogenesis of chronic lung diseases and especially in conditions that display mucus obstruction, such as chronic obstructive pulmonary disease, cystic fibrosis, and non-cystic fibrosis bronchiectasis. However, our appreciation of the roles of proteases in various aspects of such diseases continues to grow. Patients with muco-obstructive lung disease experience progressive spirals of inflammation, mucostasis, airway infection and lung function decline. Some therapies exist for the treatment of these symptoms, but they are unable to halt disease progression and patients may benefit from novel adjunct therapies. In this review, we highlight how proteases act as multifunctional enzymes that are vital for normal airway homeostasis but, when their activity becomes immoderate, also directly contribute to airway dysfunction, and impair the processes that could resolve disease. We focus on how proteases regulate the state of mucus at the airway surface, impair mucociliary clearance and ultimately, promote mucostasis. We discuss how, in parallel, proteases are able to promote an inflammatory environment in the airways by mediating proinflammatory signalling, compromising host defence mechanisms and perpetuating their own proteolytic activity causing structural lung damage. Finally, we discuss some possible reasons for the clinical inefficacy of protease inhibitors to date and propose that, especially in a combination therapy approach, proteases represent attractive therapeutic targets for muco-obstructive lung diseases.

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Section: Proteases and Mucusmentioning

confidence: 99%

Proteases, Mucus, and Mucosal Immunity in Chronic Lung Disease

McKelvey

Brown

Ryan

et al. 2021

IJMS

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“…Nedd4-2, an E3 ubiquitin-protein ligase, participates in negatively regulating sodium channel expression by ubiquitination and targeting for degradation. 34 , 35 Moreover, Akt phosphorylation competes with Nedd4‐2 for the binding sites of ENaC to increase ENaC expression. 36 , 37 Consistently, rosuvastatin reduced the LPS-induced increase in Nedd4-2 protein levels, and that the beneficial effects of rosuvastatin in inhibiting Nedd4-2 protein expression were abrogated by LY294002, indicating that rosuvastatin improved ENaC and Na,K-ATPase expression through activation of the PI3K/Akt/Nedd4-2 pathway.…”

Section: Discussionmentioning

confidence: 99%

Rosuvastatin Enhances Alveolar Fluid Clearance in Lipopolysaccharide-Induced Acute Lung Injury by Activating the Expression of Sodium Channel and Na,K-ATPase via the PI3K/AKT/Nedd4-2 Pathway

Xu¹,

Yang²,

Xiang³

et al. 2021

JIR

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Background Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are devastating clinical conditions characterized by pulmonary epithelial damage and protein-rich fluid accumulation in the alveolar spaces. Statins are a class of HMG-CoA reductase inhibitors, which exert cholesterol-lowering and anti-inflammatory effects. Methods Rosuvastatin (1 mg/kg) was injected intravenously in rats 12 h before lipopolysaccharide (LPS, 10 mg/kg) administration. Eight hours later after LPS challenge, alveolar fluid clearance (AFC) was detected in rats (n = 6–8). Rosuvastatin (0.3 µmol/mL) and LPS were cultured with primary rat alveolar type II epithelial cells for 8 h. Results Rosuvastatin obviously improved AFC and attenuated lung-tissue damage in ALI model. Moreover, it enhanced AFC by increasing sodium channel and Na,K-ATPase protein expression. It also up-regulated P-Akt via reducing Nedd4-2 in vivo and in vitro. Furthermore, LY294002 blocked the increase in AFC in response to rosuvastatin. Rosuvastatin-induced AFC was found to be partly rely on sodium channel and Na,K-ATPase expression via the PI3K/AKT/Nedd4-2 pathway. Conclusion In summary, the findings of our study revealed the potential role of rosuvastatin in the management of ALI/ARDS.

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“…Cell type-specific deletion of NEDD4L in surfactant C-expressing type II lung epithelial cells increases the ENaC protein level and a cystic fibrosis-like disease phenotype [ 83 ]. Moreover, Duerr et al have reported that NEDD4L suppresses bleomycin-induced pulmonary fibrosis by degradation of ENaC and TβR using NEDD4L-conditional deletion mice [ 84 ]. NEDD4L plays an important role in normal functioning of pulmonary epithelial cells, and its dysfunction causes pulmonary fibrosis ( Table 1 ).…”

Section: Regulation Of Emt and Pulmonary Fibrosis Via Ubiquitin-protementioning

confidence: 99%

Molecular Pathogenesis of Pulmonary Fibrosis, with Focus on Pathways Related to TGF-β and the Ubiquitin-Proteasome Pathway

Inui

Sakai

Kitagawa

2021

IJMS

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Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease. During the past decade, novel pathogenic mechanisms of IPF have been elucidated that have shifted the concept of IPF from an inflammatory-driven to an epithelial-driven disease. Dysregulated repair responses induced by recurrent epithelial cell damage and excessive extracellular matrix accumulation result in pulmonary fibrosis. Although there is currently no curative therapy for IPF, two medications, pirfenidone and nintedanib, have been introduced based on understanding the pathogenesis of the disease. In this review, we discuss advances in understanding IPF pathogenesis, highlighting epithelial–mesenchymal transition (EMT), the ubiquitin-proteasome system, and endothelial cells. TGF-β is a central regulator involved in EMT and pulmonary fibrosis. HECT-, RING finger-, and U-box-type E3 ubiquitin ligases regulate TGF-β-Smad pathway-mediated EMT via the ubiquitin-proteasome pathway. p27 degradation mediated by the SCF-type E3 ligase, Skp2, contributes to the progression of pulmonary fibrosis by promotion of either mesenchymal fibroblast proliferation, EMT, or both. In addition to fibroblasts as key effector cells in myofibroblast differentiation and extracellular matrix deposition, endothelial cells also play a role in the processes of IPF. Endothelial cells can transform into myofibroblasts; therefore, endothelial–mesenchymal transition can be another source of myofibroblasts.

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Conditional deletion of Nedd4-2 in lung epithelial cells causes progressive pulmonary fibrosis in adult mice

Cited by 56 publications

References 95 publications

Proteases, Mucus, and Mucosal Immunity in Chronic Lung Disease

Proteases, Mucus, and Mucosal Immunity in Chronic Lung Disease

Rosuvastatin Enhances Alveolar Fluid Clearance in Lipopolysaccharide-Induced Acute Lung Injury by Activating the Expression of Sodium Channel and Na,K-ATPase via the PI3K/AKT/Nedd4-2 Pathway

Molecular Pathogenesis of Pulmonary Fibrosis, with Focus on Pathways Related to TGF-β and the Ubiquitin-Proteasome Pathway

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