2. Academic Validation
  3. Nephrocystin proteins NPHP5 and Cep290 regulate BBSome integrity, ciliary trafficking and cargo delivery

Nephrocystin proteins NPHP5 and Cep290 regulate BBSome integrity, ciliary trafficking and cargo delivery

  • Hum Mol Genet. 2015 Apr 15;24(8):2185-200. doi: 10.1093/hmg/ddu738.
Marine Barbelanne 1,  Delowar Hossain 2,  David Puth Chan 3,  Johan Peränen 4,  William Y Tsang 5
Affiliations

Affiliations

  • 1 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.
  • 2 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.
  • 3 Institut de recherches cliniques de Montréal, 110 Avenue des Pins Ouest, Montréal, QC H2W 1R7, Canada.
  • 4 Institute of Biotechnology, University of Helsinki, Helsinki 00014, Finland.
  • 5 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.
PMID: 25552655 DOI: 10.1093/hmg/ddu738
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.

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