2. Academic Validation
  3. A human ciliopathy reveals essential functions for NEK10 in airway mucociliary clearance

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

Affiliations

  • 1 Division of Pulmonary and Critical Care Medicine, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. [email protected].
  • 2 Whitehead Institute for Biomedical Research, Cambridge, MA, USA. [email protected].
  • 3 Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA. [email protected].
  • 4 Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA. [email protected].
  • 5 Koch Institute for Integrative Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA. [email protected].
  • 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. [email protected].
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 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.

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