title: Nephrocystin proteins NPHP5 and Cep290 regulate BBSome integrity, ciliary trafficking and cargo delivery.
abstract: Proper functioning of cilia, hair-like structures responsible for sensation and locomotion, requires nephrocystin-5 (NPHP5) and a multi-subunit complex called the Bardet-Biedl syndrome (BBS)ome, but their precise relationship is not understood. The BBSome is involved in the trafficking of membrane cargos to cilia. While it is known that a loss of any single subunit prevents ciliary trafficking of the BBSome and its cargos, the mechanisms underlying ciliary entry of this complex are not well characterized. Here, we report that a transition zone protein NPHP5 contains two separate BBS-binding sites and interacts with the BBSome to mediate its integrity. Depletion of NPHP5, or expression of NPHP5 mutant missing one binding site, specifically leads to dissociation of BBS2 and BBS5 from the BBSome and loss of ciliary BBS2 and BBS5 without compromising the ability of the other subunits to traffic into cilia. Depletion of Cep290, another transition zone protein that directly binds to NPHP5, causes additional dissociation of BBS8 and loss of ciliary BBS8. Furthermore, delivery of BBSome cargos, smoothened, VPAC2 and Rab8a, to the ciliary compartment is completely disabled in the absence of single BBS subunits, but is selectively impaired in the absence of NPHP5 or Cep290. These findings define a new role of NPHP5 and Cep290 in controlling integrity and ciliary trafficking of the BBSome, which in turn impinge on the delivery of ciliary cargo.
authors.affiliation: Institut de recherches cliniques de Montréal, 110 Avenue des Pins Ouest, Montréal, QC H2W 1R7, Canada, Faculté de Médecine, Université de Montréal, Montréal, QC H3C 3J7, Canada.
authors.forename: Marine
authors.initials: M
authors.lastname: Barbelanne
authors.affiliation: Institut de recherches cliniques de Montréal, 110 Avenue des Pins Ouest, Montréal, QC H2W 1R7, Canada, Division of Experimental Medicine, McGill University, Montréal, QC H3A 1A3, Canada and.
authors.forename: Delowar
authors.initials: D
authors.lastname: Hossain
authors.affiliation: Institut de recherches cliniques de Montréal, 110 Avenue des Pins Ouest, Montréal, QC H2W 1R7, Canada.
authors.forename: David Puth
authors.initials: DP
authors.lastname: Chan
authors.affiliation: Institute of Biotechnology, University of Helsinki, Helsinki 00014, Finland.
authors.forename: Johan
authors.initials: J
authors.lastname: Peränen
authors.affiliation: Institut de recherches cliniques de Montréal, 110 Avenue des Pins Ouest, Montréal, QC H2W 1R7, Canada, Faculté de Médecine, Université de Montréal, Montréal, QC H3C 3J7, Canada, Division of Experimental Medicine, McGill University, Montréal, QC H3A 1A3, Canada and william.tsang@ircm.qc.ca.
authors.forename: William Y
authors.initials: WY
authors.lastname: Tsang
mesh_terms: D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism*; D020788:Bardet-Biedl Syndrome / Q000235:genetics / Q000378:metabolism*; D002148:Calmodulin-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins; D002923:Cilia / Q000235:genetics / Q000378:metabolism*; D003598:Cytoskeletal Proteins; D006801:Humans; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport
chemical_list: D000951:Antigens, Neoplasm; D002148:Calmodulin-Binding Proteins; D018797:Cell Cycle Proteins; C493903:Cep290 protein, human; D003598:Cytoskeletal Proteins; C498171:IQCB1 protein, human; D046912:Multiprotein Complexes; D009363:Neoplasm Proteins