Cell
Volume 168, Issues 1–2, 12 January 2017, Pages 252-263.e14
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Article
An Actin Network Dispatches Ciliary GPCRs into Extracellular Vesicles to Modulate Signaling

https://doi.org/10.1016/j.cell.2016.11.036Get rights and content
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Highlights

  • Signal-dependent exit of GPCRs from cilia proceeds through retrieval or ectocytosis

  • GPCRs that cannot be retrieved back into the cell are instead ectocytosed

  • Actin, myosin 6, and drebrin mediate the scission of ectosomes from cilia tips

  • Hedgehog signaling fails when both ectocytosis and retrieval are blocked

Summary

Signaling receptors dynamically exit cilia upon activation of signaling pathways such as Hedgehog. Here, we find that when activated G protein-coupled receptors (GPCRs) fail to undergo BBSome-mediated retrieval from cilia back into the cell, these GPCRs concentrate into membranous buds at the tips of cilia before release into extracellular vesicles named ectosomes. Unexpectedly, actin and the actin regulators drebrin and myosin 6 mediate ectosome release from the tip of cilia. Mirroring signal-dependent retrieval, signal-dependent ectocytosis is a selective and effective process that removes activated signaling molecules from cilia. Congruently, ectocytosis compensates for BBSome defects as ectocytic removal of GPR161, a negative regulator of Hedgehog signaling, permits the appropriate transduction of Hedgehog signals in Bbs mutants. Finally, ciliary receptors that lack retrieval determinants such as the anorexigenic GPCR NPY2R undergo signal-dependent ectocytosis in wild-type cells. Our data show that signal-dependent ectocytosis regulates ciliary signaling in physiological and pathological contexts.

Keywords

cilia
extracellular vesicles
GPCR
Hedgehog
BBSome
exosomes
actin
myosin 6
drebrin

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