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

Nature Communications
Sumeda NandadasaSuneel S Apte

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.

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Citations

Jan 26, 2020·Cells·I Collins, A K T Wann
Dec 23, 2020·Open Biology·Salvatore Santamaria, Rens de Groot
Jan 2, 2021·Bone Research·Wenjing YuSongtao Shi
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Oct 16, 2021·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Cameron J FairfieldEwen M Harrison

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Methods Mentioned

BETA
confocal microscopy
electron microscopy
transfection
dotplots
glycosylation
gene trap
genotyping
PCR
confocal
fluorescence imaging

Software Mentioned

LI
Leica LAS X
Volocity 3D
GraphPad Prism
Leica Application Suite
NRecon
COR Image Studio
Hyvolution
Drishti
ImageJ

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