title: An Actin Network Dispatches Ciliary GPCRs into Extracellular Vesicles to Modulate Signaling.
abstract: 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.
authors.affiliation: Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305-5345, USA.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Nager
authors.affiliation: Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305-5345, USA.
authors.forename: Jaclyn S
authors.initials: JS
authors.lastname: Goldstein
authors.affiliation: Laboratorio de Neurobiología Comparada, Instituto Cavanilles, Universitat de València, CIBERNED, 46980 Valencia, Spain; Unidad Mixta de Esclerosis Múltiple y Neurorregeneración, IIS Hospital La Fe-UVEG, 46026 Valencia, Spain.
authors.forename: Vicente
authors.initials: V
authors.lastname: Herranz-Pérez
authors.affiliation: Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305-5345, USA.
authors.forename: Didier
authors.initials: D
authors.lastname: Portran
authors.affiliation: Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305-5345, USA.
authors.forename: Fan
authors.initials: F
authors.lastname: Ye
authors.affiliation: Laboratorio de Neurobiología Comparada, Instituto Cavanilles, Universitat de València, CIBERNED, 46980 Valencia, Spain; Unidad Mixta de Esclerosis Múltiple y Neurorregeneración, IIS Hospital La Fe-UVEG, 46026 Valencia, Spain.
authors.forename: Jose Manuel
authors.initials: JM
authors.lastname: Garcia-Verdugo
authors.affiliation: Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305-5345, USA. Electronic address: nachury@gmail.com.
authors.forename: Maxence V
authors.initials: MV
authors.lastname: Nachury
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D002923:Cilia / Q000378:metabolism*; D000067128:Extracellular Vesicles / Q000378:metabolism*; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008855:Microscopy, Electron, Scanning; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D017481:Receptors, Somatostatin / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D000199:Actins; D043562:Receptors, G-Protein-Coupled; D017481:Receptors, Somatostatin; C103631:somatostatin receptor 3
keywords: BBSome; GPCR; Hedgehog; actin; cilia; drebrin; exosomes; extracellular vesicles; myosin 6