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

Nat Med. 2020 Feb;26(2):244-251. doi: 10.1038/s41591-019-0730-x.

Raghu R Chivukula ¹ ² ³ ⁴ ⁵, Daniel T Montoro ⁶, Hui Min Leung ⁷ ⁸, Jason Yang ⁹ ¹⁰ ⁶ ¹¹, Hanan E Shamseldin ¹², Martin S Taylor ⁹ ¹⁰ ⁶ ¹¹ ¹³, Gerard W Dougherty ¹⁴, Maimoona A Zariwala ¹⁵, Johnny Carson ¹⁶, M Leigh Anne Daniels ¹⁷, Patrick R Sears ¹⁸, Katharine E Black ¹⁹, Lida P Hariri ¹³, Ibrahim Almogarri ²⁰, Evgeni M Frenkel ⁹ ¹⁰ ⁶ ¹¹, Vladimir Vinarsky ¹⁹, Heymut Omran ¹⁴, Michael R Knowles ¹⁸ ²¹, Guillermo J Tearney ⁷ ⁸ ¹³ ²², Fowzan S Alkuraya ²³, David M Sabatini ⁹ ¹⁰ ⁶ ¹¹

Affiliations

1 Division of Pulmonary and Critical Care Medicine, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. raghu@wi.mit.edu.
2 Whitehead Institute for Biomedical Research, Cambridge, MA, USA. raghu@wi.mit.edu.
3 Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA. raghu@wi.mit.edu.
4 Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA. raghu@wi.mit.edu.
5 Koch Institute for Integrative Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA. raghu@wi.mit.edu.
6 Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA.
7 Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA, USA.
8 Harvard Medical School, Boston, MA, USA.
9 Whitehead Institute for Biomedical Research, Cambridge, MA, USA.
10 Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
11 Koch Institute for Integrative Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
12 Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
13 Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
14 Department of General Pediatrics, University Children's Hospital Muenster, Münster, Germany.
15 Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
16 Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
17 Division of Pulmonary Diseases and Critical Care Medicine, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
18 Cystic Fibrosis/Pulmonary Research and Treatment Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
19 Division of Pulmonary and Critical Care Medicine, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
20 Department of Pediatrics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
21 Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
22 Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA, USA.
23 Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia. falkuraya@kfshrc.edu.sa.

PMID: 31959991 DOI: 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 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 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.

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