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

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

Research output: Contribution to journalArticle

2 Citations (Scopus)

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.

Original languageEnglish
Article number953
JournalNature communications
Volume10
Issue number1
DOIs
Publication statusPublished - 2019 Dec 1

Fingerprint

Cilia
Metalloproteases
Clustered Regularly Interspaced Short Palindromic Repeats
Furin
mutagenesis
Clathrin
Yolk Sac
Mutagenesis
Molecules
Heparitin Sulfate
Hedgehogs
regulators
Growth
Endocytosis
deactivation
mice
molecules
Microscopy
sulfates
Microscopic examination

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Nandadasa, Sumeda ; Kraft, Caroline M. ; Wang, Lauren W. ; O’Donnell, Anna ; Patel, Rushabh ; Gee, Heon Yung ; Grobe, Kay ; Cox, Timothy C. ; Hildebrandt, Friedhelm ; Apte, Suneel S. / Secreted metalloproteases ADAMTS9 and ADAMTS20 have a non-canonical role in ciliary vesicle growth during ciliogenesis. In: Nature communications. 2019 ; Vol. 10, No. 1.
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Nandadasa, S, Kraft, CM, Wang, LW, O’Donnell, A, Patel, R, Gee, HY, Grobe, K, Cox, TC, Hildebrandt, F & Apte, SS 2019, 'Secreted metalloproteases ADAMTS9 and ADAMTS20 have a non-canonical role in ciliary vesicle growth during ciliogenesis', Nature communications, vol. 10, no. 1, 953. https://doi.org/10.1038/s41467-019-08520-7

Secreted metalloproteases ADAMTS9 and ADAMTS20 have a non-canonical role in ciliary vesicle growth during ciliogenesis. / Nandadasa, Sumeda; Kraft, Caroline M.; Wang, Lauren W.; O’Donnell, Anna; Patel, Rushabh; Gee, Heon Yung; Grobe, Kay; Cox, Timothy C.; Hildebrandt, Friedhelm; Apte, Suneel S.

In: Nature communications, Vol. 10, No. 1, 953, 01.12.2019.

Research output: Contribution to journalArticle

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AU - Wang, Lauren W.

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AU - Patel, Rushabh

AU - Gee, Heon Yung

AU - Grobe, Kay

AU - Cox, Timothy C.

AU - Hildebrandt, Friedhelm

AU - Apte, Suneel S.

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