The Ciliopathy Protein CC2D2A Associates with NINL and Functions in RAB8-MICAL3-Regulated Vesicle Trafficking

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Ciliopathies are a group of disorders caused by dysfunction of primary cilia, ubiquitous organelles involved in signal transduction. Mutations in CC2D2A cause two ciliopathies, Joubert and Meckel syndromes, and result in loss of ciliary protein localization. The mechanism by which CC2D2A, located at the ciliary transition zone, controls ciliary protein composition and its link to vesicular trafficking of incoming cargo remain largely unknown. Here, we identify a series of physical interactions linking CC2D2A to vesicular trafficking controlled by the small GTPase RAB8, suggesting a new model, whereby CC2D2A provides a specific docking point for ciliary-bound vesicles at the entrance to the ciliary compartment. We first identify NINL as a physical and genetic interaction partner of CC2D2A, show that both proteins co-localize at the entrance to the cilium and demonstrate that absence of Ninl or Cc2d2a result in similar retinal phenotypes in zebrafish, including mislocalization of Rab8. We further identify MICAL3, a protein known to bind RAB8, as another NINL interaction partner, thus linking CC2D2A to RAB8A-controlled trafficking. Finally, we describe an individual with Joubert syndrome, in whom combined CC2D2A and NINL mutations result in an enhanced phenotype, illustrating the impact of the detected interaction on the disease.

Vyšlo v časopise: The Ciliopathy Protein CC2D2A Associates with NINL and Functions in RAB8-MICAL3-Regulated Vesicle Trafficking. PLoS Genet 11(10): e32767. doi:10.1371/journal.pgen.1005575
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1005575

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