Journal Article

A human ciliopathy reveals essential functions for NEK10 in airway mucociliary clearance

Montoro, Daniel T., Frenkel, Evgeni M., Omran, Heymut, Hariri, Lida P., Yang, Jason, Taylor, Martin S., Tearney, Guillermo J., Alkuraya, Fowzan S., Shamseldin, Hanan E., Black, Katharine E., Almogarri, Ibrahim, Vinarsky, Vladimir, Daniels, M. Leigh Anne, Sabatini, David M., Zariwala, Maimoona A., Leung, Hui Min, Dougherty, Gerard W., Chivukula, Raghu R., Sears, Patrick R., Carson, Johnny, Knowles, Michael R.

2020

Overview

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 cells 1 , 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 immunodeficiencies 3 . Previous studies have identified mutations that affect ciliary structure and nucleation in PCD 4 , 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. Inactivating mutations in a protein kinase, NEK10, cause a genetic bronchiectasis syndrome in humans that is characterized by short motile cilia and impaired mucociliary transport.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/208/1516 / 631/80/304 / Adolescent / Adult / Airway (Medicine) / Beat frequencies / Biomedical and Life Sciences / Biomedicine / Bronchiectasis / Cancer Research / Cell Separation / Child / Cilia / Cilia and ciliary motion / Ciliopathies - immunology / Ciliopathies - metabolism / Cystic fibrosis / Cystic Fibrosis Transmembrane Conductance Regulator - metabolism / Deactivation / Epithelial Cells - metabolism / Exome / Female / Flow Cytometry / Genetic modification / Goblet cells / HEK293 Cells / Heredity / Homozygote / Humans / Immune clearance / Infectious Diseases / Kinases / Letter / Mammals / Medical examination / Metabolic Diseases / Microscopy, Phase-Contrast / Microscopy, Video / Molecular Medicine / Mucociliary Clearance / Mucus / Mutation / Neurosciences / NIMA-Related Kinases - metabolism / Nucleation / Phenotype / Primary ciliary dyskinesia / Protein kinase / Proteins / Proteome / Proteomes / Respiratory diseases / Respiratory mucosa / Respiratory System / Respiratory tract / Stem cells / Therapeutic applications / Therapeutic targets / Tomography, X-Ray Computed / Transport / X-Ray Microtomography / Young Adult