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

Author

Listed:
  • Sumeda Nandadasa

    (Cleveland Clinic Lerner Research Institute)

  • Caroline M. Kraft

    (Cleveland Clinic Lerner Research Institute)

  • Lauren W. Wang

    (Cleveland Clinic Lerner Research Institute)

  • Anna O’Donnell

    (Cleveland Clinic Lerner Research Institute)

  • Rushabh Patel

    (Cleveland Clinic Lerner Research Institute)

  • Heon Yung Gee

    (Yonsei University College of Medicine)

  • Kay Grobe

    (University of Münster)

  • Timothy C. Cox

    (University of Washington
    UMKC School of Dentistry)

  • Friedhelm Hildebrandt

    (Harvard Medical School)

  • Suneel S. Apte

    (Cleveland Clinic Lerner Research Institute)

Abstract

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.

Suggested Citation

  • Sumeda Nandadasa & Caroline M. Kraft & Lauren W. Wang & Anna O’Donnell & Rushabh Patel & Heon Yung Gee & Kay Grobe & Timothy C. Cox & Friedhelm Hildebrandt & Suneel S. Apte, 2019. "Secreted metalloproteases ADAMTS9 and ADAMTS20 have a non-canonical role in ciliary vesicle growth during ciliogenesis," Nature Communications, Nature, vol. 10(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-08520-7
    DOI: 10.1038/s41467-019-08520-7
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