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

Abstract

Ciliopathies are a group of human disorders caused by dysfunction of primary cilia, ubiquitous microtubule-based organelles involved in transduction of extra-cellular signals to the cell. This function requires the concentration of receptors and channels in the ciliary membrane, which is achieved by complex trafficking mechanisms, in part controlled by the small GTPase RAB8, and by sorting at the transition zone located at the entrance of the ciliary compartment. Mutations in the transition zone gene CC2D2A cause the related Joubert and Meckel syndromes, two typical ciliopathies characterized by central nervous system malformations, and result in loss of ciliary localization of multiple proteins in various models. The precise mechanisms by which CC2D2A and other transition zone proteins control protein entrance into the cilium and how they are linked to vesicular trafficking of incoming cargo remain largely unknown. In this work, we identify the centrosomal protein NINL as a physical interaction partner of CC2D2A. NINL partially co-localizes with CC2D2A at the base of cilia and ninl knockdown in zebrafish leads to photoreceptor outer segment loss, mislocalization of opsins and vesicle accumulation, similar to cc2d2a-/- phenotypes. Moreover, partial ninl knockdown in cc2d2a-/- embryos enhances the retinal phenotype of the mutants, indicating a genetic interaction in vivo, for which an illustration is found in patients from a Joubert Syndrome cohort. Similar to zebrafish cc2d2a mutants, ninl morphants display altered Rab8a localization. Further exploration of the NINL-associated interactome identifies MICAL3, a protein known to interact with Rab8 and to play an important role in vesicle docking and fusion. Together, these data support a model where CC2D2A associates with NINL to provide a docking point for cilia-directed cargo vesicles, suggesting a mechanism by which transition zone proteins can control the protein content of the ciliary compartment.

• Authors: Ruxandra Bachmann-Gagescu, Margo Dona, Lisette Hetterschijt, Edith Tonnaer, Theo Peters, Erik de Vrieze, Dorus A Mans, Sylvia E C van Beersum, Ian G Phelps, Heleen H Arts, Jan E Keunen, Marius Ueffing, Ronald Roepman, Karsten Boldt, Dan Doherty, Cecilia B Moens, Stephan C F Neuhauss, Hannie Kremer, Erwin van Wijk
• Journal: PLoS genetics (PLoS Genet) Vol. 11 Issue 10 Pg. e1005575 (Oct 2015) ISSN: 1553-7404 [Electronic] United States
• PMID: 26485645 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• CC2D2A protein, human
• Cytoskeletal Proteins
• Microtubule-Associated Proteins
• NINL protein, human
• Nuclear Proteins
• Proteins
• MICAL3 protein, human
• Mixed Function Oxygenases
• RAB8A protein, human
• rab GTP-Binding Proteins

Topics

• Abnormalities, Multiple (genetics, metabolism, pathology)
• Animals
• Cerebellum (abnormalities, metabolism, pathology)
• Cilia (genetics, metabolism, pathology)
• Ciliary Motility Disorders (genetics, metabolism, pathology)
• Cytoskeletal Proteins
• Encephalocele (genetics, metabolism, pathology)
• Eye Abnormalities (genetics, metabolism, pathology)
• Gene Knockdown Techniques
• Humans
• Kidney Diseases, Cystic (genetics, metabolism, pathology)
• Microtubule-Associated Proteins (genetics, metabolism)
• Mixed Function Oxygenases (genetics, metabolism)
• Mutation
• Nuclear Proteins (genetics, metabolism)
• Polycystic Kidney Diseases (genetics, metabolism, pathology)
• Protein Transport (genetics)
• Proteins (genetics, metabolism)
• Retina (abnormalities, metabolism, pathology)
• Retinitis Pigmentosa
• Signal Transduction
• Zebrafish
• rab GTP-Binding Proteins (genetics, metabolism)