A human ciliopathy reveals essential functions for NEK10 in airway mucociliary clearance
Name
nihms-1546020.pdf
Description
Accepted version
Size
5.54 MB
Format
Adobe PDF
Checksum (MD5)
71eca8a40b13f8f015449ac156efb0a2
Author(s)
Chivukula, Raghu R
Montoro, Daniel T
Leung, Hui Min
Yang, Jason
Shamseldin, Hanan E
Taylor, Martin S
Dougherty, Gerard W
Zariwala, Maimoona A
Carson, Johnny
Daniels, M Leigh Anne
Date Issued
2020
Journal
Nature Medicine
Publisher
Springer Science and Business Media LLC
Version
Author's final manuscript
Abstract
© 2020, The Author(s), under exclusive licence to Springer Nature America, Inc. 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.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Whitehead Institute for Biomedical Research
Howard Hughes Medical Institute
Koch Institute for Integrative Cancer Research at MIT
Harvard University--MIT Division of Health Sciences and Technology
Terms of Use
Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.
Persistent DSpace Link
DOI of Published Version
10.1038/S41591-019-0730-X
