Secreted metalloproteases ADAMTS9 and ADAMTS20 have a non-canonical role in ciliary vesicle growth during ciliogenesis

Nat Commun. 2019 Feb 27;10(1):953. doi: 10.1038/s41467-019-08520-7.


Although hundreds of cytosolic or transmembrane molecules form the primary cilium, few secreted molecules are known to contribute to ciliogenesis. Here, homologous secreted metalloproteases ADAMTS9 and ADAMTS20 are identified as ciliogenesis regulators that act intracellularly. Secreted and furin-processed ADAMTS9 bound heparan sulfate and was internalized by LRP1, LRP2 and clathrin-mediated endocytosis to be gathered in Rab11 vesicles with a unique periciliary localization defined by super-resolution microscopy. CRISPR-Cas9 inactivation of ADAMTS9 impaired ciliogenesis in RPE-1 cells, which was restored by catalytically active ADAMTS9 or ADAMTS20 acting in trans, but not by their proteolytically inactive mutants. Their mutagenesis in mice impaired neural and yolk sac ciliogenesis, leading to morphogenetic anomalies resulting from impaired hedgehog signaling, which is transduced by primary cilia. In addition to their cognate extracellular proteolytic activity, ADAMTS9 and ADAMTS20 thus have an additional proteolytic role intracellularly, revealing an unexpected regulatory dimension in ciliogenesis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAMTS Proteins / deficiency
  • ADAMTS Proteins / genetics
  • ADAMTS Proteins / metabolism*
  • ADAMTS9 Protein / deficiency
  • ADAMTS9 Protein / genetics
  • ADAMTS9 Protein / metabolism*
  • Animals
  • Cell Line
  • Cilia / metabolism*
  • Cilia / ultrastructure*
  • Endocytosis
  • Gene Knockout Techniques
  • Humans
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Microscopy, Electron, Scanning
  • Models, Biological
  • Mutation
  • Neural Tube Defects / embryology
  • Neural Tube Defects / genetics
  • Neural Tube Defects / metabolism
  • Proteolysis
  • Signal Transduction
  • Versicans / genetics
  • Versicans / metabolism
  • Yolk Sac / embryology
  • Yolk Sac / metabolism


  • VCAN protein, human
  • Vcan protein, mouse
  • Versicans
  • ADAMTS Proteins
  • ADAMTS20 protein, human
  • ADAMTS9 Protein
  • ADAMTS9 protein, human
  • Adamts20 protein, mouse
  • Adamts9 protein, mouse