title: Regulation of polycystin-1 ciliary trafficking by motifs at its C-terminus and polycystin-2 but not by cleavage at the GPS site.
abstract: Failure to localize membrane proteins to the primary cilium causes a group of diseases collectively named ciliopathies. Polycystin-1 (PC1, also known as PKD1) is a large ciliary membrane protein defective in autosomal dominant polycystic kidney disease (ADPKD). Here, we developed a large set of PC1 expression constructs and identified multiple sequences, including a coiled-coil motif in the C-terminal tail of PC1, regulating full-length PC1 trafficking to the primary cilium. Ciliary trafficking of wild-type and mutant PC1 depends on the dose of polycystin-2 (PC2, also known as PKD2), and the formation of a PC1-PC2 complex. Modulation of the ciliary trafficking module mediated by the VxP ciliary-targeting sequence and Arf4 and Asap1 does not affect the ciliary localization of full-length PC1. PC1 also promotes PC2 ciliary trafficking. PC2 mutations truncating its C-terminal tail but not those changing the VxP sequence to AxA or impairing the pore of the channel, leading to a dead channel, affect PC1 ciliary trafficking. Cleavage at the GPCR proteolytic site (GPS) of PC1 is not required for PC1 trafficking to cilia. We propose a mutually dependent model for the ciliary trafficking of PC1 and PC2, and that PC1 ciliary trafficking is regulated by multiple cis-acting elements. As all pathogenic PC1 mutations tested here are defective in ciliary trafficking, ciliary trafficking might serve as a functional read-out for ADPKD.
authors.affiliation: Harvard Center for Polycystic Kidney Disease Research and Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Su
authors.affiliation: Harvard Center for Polycystic Kidney Disease Research and Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Maoqing
authors.initials: M
authors.lastname: Wu
authors.affiliation: Harvard Center for Polycystic Kidney Disease Research and Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Yao
authors.affiliation: Harvard Center for Polycystic Kidney Disease Research and Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Wassim
authors.initials: W
authors.lastname: El-Jouni
authors.affiliation: Harvard Center for Polycystic Kidney Disease Research and Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA Kidney Disease Center, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, People's Republic of China.
authors.forename: Chong
authors.initials: C
authors.lastname: Luo
authors.affiliation: Harvard Center for Polycystic Kidney Disease Research and Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Azadeh
authors.initials: A
authors.lastname: Tabari
authors.affiliation: Harvard Center for Polycystic Kidney Disease Research and Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA zhou@rics.bwh.harvard.edu.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhou
mesh_terms: D000818:Animals; D002923:Cilia / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D007685:Kidney Tubules, Collecting / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D050396:TRPP Cation Channels / Q000235:genetics / Q000378:metabolism*
chemical_list: D050396:TRPP Cation Channels
keywords: Cilium; Polycystin-1; Polycystin-2; Trafficking