title: Ciliary membrane proteins traffic through the Golgi via a Rabep1/GGA1/Arl3-dependent mechanism.
abstract: Primary cilia contain specific receptors and channel proteins that sense the extracellular milieu. Defective ciliary function causes ciliopathies such as autosomal dominant polycystic kidney disease (ADPKD). However, little is known about how large ciliary transmembrane proteins traffic to the cilia. Polycystin-1 (PC1) and -2 (PC2), the two ADPKD gene products, are large transmembrane proteins that co-localize to cilia where they act to control proper tubular diameter. Here we describe that PC1 and PC2 must interact and form a complex to reach the trans-Golgi network (TGN) for subsequent ciliary targeting. PC1 must also be proteolytically cleaved at a GPS site for this to occur. Using yeast two-hybrid screening coupled with a candidate approach, we identify a Rabep1/GGA1/Arl3-dependent ciliary targeting mechanism, whereby Rabep1 couples the polycystin complex to a GGA1/Arl3-based ciliary trafficking module at the TGN. This study provides novel insights into the ciliary trafficking mechanism of membrane proteins.
authors.affiliation: Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
authors.forename: Hyunho
authors.initials: H
authors.lastname: Kim
authors.affiliation: Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
authors.forename: Hangxue
authors.initials: H
authors.lastname: Xu
authors.affiliation: Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
authors.forename: Qin
authors.initials: Q
authors.lastname: Yao
authors.affiliation: Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
authors.forename: Weizhe
authors.initials: W
authors.lastname: Li
authors.affiliation: Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Huang
authors.affiliation: Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
authors.forename: Patricia
authors.initials: P
authors.lastname: Outeda
authors.affiliation: Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: Valeriu
authors.initials: V
authors.lastname: Cebotaru
authors.affiliation: Division of Genetics and Cell Biology, San Raffaele Scientific Institute, 20132 Milan, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Chiaravalli
authors.affiliation: Division of Genetics and Cell Biology, San Raffaele Scientific Institute, 20132 Milan, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Boletta
authors.affiliation: Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: Klaus
authors.initials: K
authors.lastname: Piontek
authors.affiliation: National Institute of Diabetes and Digestive and Kidney Disease, National Institute of Health, Bethesda, Maryland 20892, USA.
authors.forename: Gregory G
authors.initials: GG
authors.lastname: Germino
authors.affiliation: Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Weinman
authors.affiliation: Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
authors.forename: Terry
authors.initials: T
authors.lastname: Watnick
authors.affiliation: Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Qian
mesh_terms: D020727:ADP-Ribosylation Factors / Q000235:genetics / Q000378:metabolism*; D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002923:Cilia / Q000235:genetics / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D011485:Protein Binding; D021381:Protein Transport; D050396:TRPP Cation Channels / Q000235:genetics / Q000378:metabolism*; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism*; D021601:trans-Golgi Network / Q000235:genetics / Q000378:metabolism*
chemical_list: D020727:ADP-Ribosylation Factors; D033942:Adaptor Proteins, Vesicular Transport; D008565:Membrane Proteins; D050396:TRPP Cation Channels; D033921:Vesicular Transport Proteins; C000603325:GGA1 protein, mouse; C486276:Rabep1 protein, mouse; C490248:Arl3 protein, mouse