A human ciliopathy reveals essential functions for NEK10 in airway mucociliary clearance
- 20 January 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Medicine
- Vol. 26 (2), 244-251
- https://doi.org/10.1038/s41591-019-0730-x
Abstract
Mucociliary clearance, the physiological process by which mammalian conducting airways expel pathogens and unwanted surface materials from the respiratory tract, depends on the coordinated function of multiple specialized cell types, including basal stem cells, mucus-secreting goblet cells, motile ciliated cells, cystic fibrosis transmembrane conductance regulator (CFTR)-rich ionocytes, and immune cells1,2. Bronchiectasis, a syndrome of pathological airway dilation associated with impaired mucociliary clearance, may occur sporadically or as a consequence of Mendelian inheritance, for example in cystic fibrosis, primary ciliary dyskinesia (PCD), and select immunodeficiencies3. Previous studies have identified mutations that affect ciliary structure and nucleation in PCD4, but the regulation of mucociliary transport remains incompletely understood, and therapeutic targets for its modulation are lacking. Here we identify a bronchiectasis syndrome caused by mutations that inactivate NIMA-related kinase 10 (NEK10), a protein kinase with previously unknown in vivo functions in mammals. Genetically modified primary human airway cultures establish NEK10 as a ciliated-cell-specific kinase whose activity regulates the motile ciliary proteome to promote ciliary length and mucociliary transport but which is dispensable for normal ciliary number, radial structure, and beat frequency. Together, these data identify a novel and likely targetable signaling axis that controls motile ciliary function in humans and has potential implications for other respiratory disorders that are characterized by impaired mucociliary clearance.This publication has 59 references indexed in Scilit:
- Fiji: an open-source platform for biological-image analysisNature Methods, 2012
- Imaging the subcellular structure of human coronary atherosclerosis using micro–optical coherence tomographyNature Medicine, 2011
- Functional characterization of putative cilia genes by high-content analysisMolecular Biology of the Cell, 2011
- Ciliogenesis: building the cell's antennaNature Reviews Molecular Cell Biology, 2011
- NEK1 Mutations Cause Short-Rib Polydactyly Syndrome Type MajewskiAmerican Journal of Human Genetics, 2011
- Nek10 Mediates G2/M Cell Cycle Arrest and MEK Autoactivation in Response to UV IrradiationMolecular and Cellular Biology, 2011
- An Autoinhibitory Tyrosine Motif in the Cell-Cycle-Regulated Nek7 Kinase Is Released through Binding of Nek9Molecular Cell, 2009
- A microtubule depolymerizing kinesin functions during both flagellar disassembly and flagellar assembly in ChlamydomonasProceedings of the National Academy of Sciences of the United States of America, 2009
- Members of the NIMA-related Kinase Family Promote Disassembly of Cilia by Multiple MechanismsMolecular Biology of the Cell, 2006
- An approach to correlate tandem mass spectral data of peptides with amino acid sequences in a protein databaseJournal of the American Society for Mass Spectrometry, 1994