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

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, CFTR-rich ionocytes, and immune cells. Bronchiectasis, a syndrome of pathological airway dilation associated with impaired mucociliary clearance, may occur sporadically or with Mendelian inheritance, such as in cystic fibrosis (CF), primary ciliary dyskinesia (PCD), and select immunodeficiencies. Prior studies have identified mutations affecting ciliary structure and nucleation in PCD4, but the regulation of mucociliary transport remains incompletely understood and therapeutic targets for modulating it are lacking. Herein we identify a bronchiectasis syndrome caused by inactivating mutations in NEK10, a protein kinase with previously unknown in vivo function 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 which controls motile ciliary function in humans and has potential implications for other respiratory disorders characterized by impaired mucociliary clearance.