miR449 Protects Airway Regeneration by Controlling AURKA/HDAC6-Mediated Ciliary Disassembly

2022 | journal article; research paper. A publication with affiliation to the University of Göttingen.

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​miR449 Protects Airway Regeneration by Controlling AURKA/HDAC6-Mediated Ciliary Disassembly​
Wildung, M.; Herr, C.; Riedel, D. ; Wiedwald, C.; Moiseenko, A.; Ramírez, F. & Tasena, H. et al.​ (2022) 
International Journal of Molecular Sciences23(14) pp. 7749​.​ DOI: https://doi.org/10.3390/ijms23147749 

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Wildung, Merit; Herr, Christian; Riedel, Dietmar ; Wiedwald, Cornelia; Moiseenko, Alena; Ramírez, Fidel; Tasena, Hataitip; Heimerl, Maren; Alevra, Mihai; Movsisyan, Naira; Lizé, Muriel ; Schuldt, Maike; Volceanov-Hahn, Larisa; Provoost, Sharen; Nöthe-Menchen, Tabea; Urrego, Diana; Freytag, Bernard; Wallmeier, Julia; Beisswenger, Christoph; Bals, Robert; van den Berge, Maarten; Timens, Wim; Hiemstra, Pieter S.; Brandsma, Corry-Anke; Maes, Tania; Andreas, Stefan ; Heijink, Irene H.; Pardo, Luis A. 
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.
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International Journal of Molecular Sciences 
Klinik für Kardiologie und Pneumologie ; Universitätsmedizin Göttingen ; Institut für Molekulare Onkologie ; Max-Planck-Institut für Multidisziplinäre Naturwissenschaften ; Institut für Neuro- und Sinnesphysiologie 
Deutsche Forschungsgemeinschaft
UMG Goettingen
Interdisziplinaeres Zentrum für Klinische Forschung (IZKF) Muenster
University of Muenster Medical School
Belgian Interuniversity Attraction Poles
Research foundation Flanders (FWO)



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