Please use this identifier to cite or link to this item:
doi:10.22028/D291-36906
Title: | miR449 Protects Airway Regeneration by Controlling AURKA/HDAC6-Mediated Ciliary Disassembly |
Author(s): | Wildung, Merit Herr, Christian Riedel, Dietmar Wiedwald, Cornelia Moiseenko, Alena Ramírez, Fidel Tasena, Hataitip Heimerl, Maren Alevra, Mihai Movsisyan, Naira 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. Lizé, Muriel |
Language: | English |
Title: | International Journal of Molecular Sciences |
Volume: | 23 |
Issue: | 14 |
Publisher/Platform: | MDPI |
Year of Publication: | 2022 |
Free key words: | COPD miR449 ciliogenesis airway lung CDC20B microRNA miR449a |
DDC notations: | 610 Medicine and health |
Publikation type: | Journal Article |
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. |
DOI of the first publication: | 10.3390/ijms23147749 |
Link to this record: | urn:nbn:de:bsz:291--ds-369060 hdl:20.500.11880/33600 http://dx.doi.org/10.22028/D291-36906 |
ISSN: | 1422-0067 |
Date of registration: | 8-Aug-2022 |
Description of the related object: | Supplementary Materials |
Related object: | https://www.mdpi.com/article/10.3390/ijms23147749/s1 |
Faculty: | M - Medizinische Fakultät |
Department: | M - Innere Medizin |
Professorship: | M - Prof. Dr. Robert Bals |
Collections: | SciDok - Der Wissenschaftsserver der Universität des Saarlandes |
Files for this record:
File | Description | Size | Format | |
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ijms-23-07749-v3.pdf | 4,88 MB | Adobe PDF | View/Open |
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