miR449 Protects Airway Regeneration by Controlling AURKA/HDAC6-Mediated Ciliary Disassembly
| Autor: | Merit Wildung, Christian Herr, Dietmar Riedel, Cornelia Wiedwald, Alena Moiseenko, Fidel Ramírez, Hataitip Tasena, Maren Heimerl, Mihai Alevra, Naira Movsisyan, Maike Schuldt, Larisa Volceanov-Hahn, Sharen Provoost, Tabea Nöthe-Menchen, Diana Urrego, Bernard Freytag, Julia Wallmeier, Christoph Beisswenger, Robert Bals, Maarten van den Berge, Wim Timens, Pieter S. Hiemstra, Corry-Anke Brandsma, Tania Maes, Stefan Andreas, Irene H. Heijink, Luis A. Pardo, Muriel Lizé |
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| Přispěvatelé: | Groningen Research Institute for Asthma and COPD (GRIAC), Guided Treatment in Optimal Selected Cancer Patients (GUTS) |
| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
CDC20B
miR449 Histone Deacetylase 6 Catalysis Aurora Kinase A/genetics lung Pulmonary Disease Inorganic Chemistry Pulmonary Disease Chronic Obstructive Mice Cilia/genetics Tubulin Chronic Obstructive/genetics Medicine and Health Sciences Animals COPD Cilia Physical and Theoretical Chemistry Molecular Biology Spectroscopy Aurora Kinase A microRNA Organic Chemistry Epithelial Cells General Medicine ciliogenesis airway miR449a Pulmonary Disease Chronic Obstructive/genetics Computer Science Applications MicroRNAs MicroRNAs/genetics Tubulin/genetics |
| Zdroj: | International Journal of Molecular Sciences, 23(14):7749. MDPI AG INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES International Journal of Molecular Sciences International Journal of Molecular Sciences; Volume 23; Issue 14; Pages: 7749 International Journal of Molecular Sciences, 23(14). MDPI |
| ISSN: | 1422-0067 |
| DOI: | 10.3390/ijms23147749 |
| Popis: | Airway mucociliary regeneration and function are key players for airway defense and are impaired in chronic obstructive pulmonary disease (COPD). Using transcriptome analysis in COPD-derived bronchial biopsies, we observed a positive correlation between cilia-related genes and microRNA-449 (miR449). In vitro, miR449 was strongly increased during airway epithelial mucociliary differentiation. In vivo, miR449 was upregulated during recovery from chemical or infective insults. miR0449−/− mice (both alleles are deleted) showed impaired ciliated epithelial regeneration after naphthalene and Haemophilus influenzae exposure, accompanied by more intense inflammation and emphysematous manifestations of COPD. The latter occurred spontaneously in aged miR449−/− mice. We identified Aurora kinase A and its effector target HDAC6 as key mediators in miR449-regulated ciliary homeostasis and epithelial regeneration. Aurora kinase A is downregulated upon miR449 overexpression in vitro and upregulated in miR449−/− mouse lungs. Accordingly, imaging studies showed profoundly altered cilia length and morphology accompanied by reduced mucociliary clearance. Pharmacological inhibition of HDAC6 rescued cilia length and coverage in miR449−/− cells, consistent with its tubulin-deacetylating function. Altogether, our study establishes a link between miR449, ciliary dysfunction, and COPD pathogenesis. |
| Databáze: | OpenAIRE |
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