6533b828fe1ef96bd1287973
RESEARCH PRODUCT
An actin network dispatches ciliary GPCRs into extracellular vesicles to modulate signaling
José Manuel García-verdugoVicente Herranz-perezFan YeDidier PortranJaclyn S. GoldsteinMaxence V. NachuryAndrew R. Nagersubject
0301 basic medicineCell signalingBBSome*myosin 6*GPCR*exosomes*HedgehogBiologyKidneyGeneral Biochemistry Genetics and Molecular BiologyArticleCell LineReceptors G-Protein-Coupled03 medical and health sciencesExtracellular VesiclesMice0302 clinical medicine*BBSomeAnimalsHumans*ciliaCiliaReceptors SomatostatinHedgehog*actinActinG protein-coupled receptorCilium*extracellular vesiclesHedgehog signaling pathwayActinsCell biology030104 developmental biologyMicroscopy Electron ScanningSignal transduction*drebrin030217 neurology & neurosurgerySignal Transductiondescription
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.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2017-01-01 |