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

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