title: Bardet-Biedl syndrome proteins 1 and 3 regulate the ciliary trafficking of polycystic kidney disease 1 protein.
abstract: Bardet-Biedl syndrome (BBS) and autosomal dominant polycystic kidney disease (ADPKD) are two genetically distinct ciliopathies but share common phenotypes such as renal cysts. Seven BBS proteins form a complex called the BBSome which is localized at the basal body or ciliary axoneme and regulates the ciliary entry or flagellar exit of several signaling molecules. Here, we demonstrate that, unlike the seven-span somatostatin receptor 3 or the leptin receptor that interacts with all subunits of the BBSome, the ADPKD protein polycystin-1 (PC1) interacts with BBS1, BBS4, BBS5 and BBS8, four of the seven components of the BBSome. Only depletion or mutation of BBS1, but not depletion of BBS5 and BBS8, or knockout of BBS4, impairs ciliary trafficking of PC1 in kidney epithelial cells. Depletion of these BBS proteins affects neither the ciliary length nor the plasma membrane targeting of PC1. Expression of a pathogenic BBS3/Arl6 mutant (T31R) that locks Arl6 in the GDP form leads to stunted cilia and inhibition of PC1 on primary cilia. We propose that the 11-span membrane protein PC1 is a BBSome cargo and that the components of the BBSome may possess subunit-specific functions. Moreover, physical interactions between the BBS and ADPKD proteins may underline the overlapping renal phenotypes in these two diseases.
authors.affiliation: Center for Polycystic Kidney Disease Research and Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA and.
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Su
authors.affiliation: Center for Polycystic Kidney Disease Research and Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA and.
authors.forename: Kaitlin
authors.initials: K
authors.lastname: Driscoll
authors.affiliation: Center for Polycystic Kidney Disease Research and Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA and.
authors.forename: Gang
authors.initials: G
authors.lastname: Yao
authors.affiliation: Center for Polycystic Kidney Disease Research and Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA and.
authors.forename: Anas
authors.initials: A
authors.lastname: Raed
authors.affiliation: Center for Polycystic Kidney Disease Research and Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA and.
authors.forename: Maoqing
authors.initials: M
authors.lastname: Wu
authors.affiliation: Molecular Medicine Unit, UCL Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK.
authors.forename: Philip L
authors.initials: PL
authors.lastname: Beales
authors.affiliation: Center for Polycystic Kidney Disease Research and Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA and zhou@rics.bwh.harvard.edu.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhou
mesh_terms: D020727:ADP-Ribosylation Factors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D002923:Cilia / Q000378:metabolism; D055786:Gene Knockout Techniques; D057809:HEK293 Cells; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport; D050396:TRPP Cation Channels / Q000235:genetics / Q000378:metabolism*
chemical_list: D020727:ADP-Ribosylation Factors; D008869:Microtubule-Associated Proteins; D050396:TRPP Cation Channels; C464790:Bbs1 protein, human; C506280:Bbs1 protein, mouse; C491435:ARL6 protein, human; C122027:Arl6 protein, mouse