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

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 BergeWim Timens, Pieter S Hiemstra, Corry-Anke Brandsma, Tania Maes, Stefan Andreas, Irene H Heijink, Luis A Pardo, Muriel Lizé*

*Corresponding author for this work

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Abstract

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.

Original languageEnglish
Article number7749
Number of pages28
JournalInternational Journal of Molecular Sciences
Volume23
Issue number14
DOIs
Publication statusPublished - 13-Jul-2022

Keywords

  • Animals
  • Aurora Kinase A/genetics
  • Cilia/genetics
  • Epithelial Cells
  • Mice
  • MicroRNAs/genetics
  • Pulmonary Disease, Chronic Obstructive/genetics
  • Tubulin/genetics

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