Human Molecular Genetics Advance Access published online on September 4, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn277
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CEP290 interacts with the centriolar satellite component PCM-1 and is required for Rab8 localization to the primary cilium
1 Department of Neurosciences, University of California San Diego, La Jolla, CA 92093, USA 2 Howard Hughes Medical Institute
* To whom correspondence should be addressed at: Leichtag Biomedical Research Building Room 482, University of California San Diego, Medical School Campus, 9500 Gilman Drive, M/C 0665, La Jolla, CA 92093 Tel: 858-822-3535, Fax: 858-822-1021, Email: jogleeson{at}ucsd.edu
Received May 30, 2008; Revised August 29, 2008; Accepted August 29, 2008
Joubert syndrome (JS) is a developmental brain disorder characterized by cerebellar vermis hypoplasia, abnormal eye movement, ataxia and mental retardation. Mutations in CEP290 are responsible for the cerebello-oculo-renal subtype of JS that includes kidney cysts and retinal degeneration, two phenotypes commonly linked to ciliopathies. CEP290 is also associated with Meckel-Gruber syndrome (MKS) and Bardet-Biedl syndrome (BBS). Here we demonstrate that CEP290 interacts with a centriolar satellite protein PCM-1, which is implicated in BBS4 function. CEP290 binds to PCM-1 and localizes to centriolar satellites in a PCM-1- and microtubule-dependent manner. Depletion of CEP290 disrupts subcellular distribution and protein complex formation of PCM-1. In accord with PCM-1’s role in microtubule organization, CEP290 knockdown causes disorganization of the cytoplasmic microtubule network. Moreover, we show that both CEP290 and PCM-1 are required for ciliogenesis and are involved in the ciliary targeting of Rab8, a small GTPase shown to collaborate with BBS protein complex to promote ciliogenesis. Our results suggest that PCM-1 is a potential mediator that may link CEP290 with BBS proteins in common molecular pathways.
Present address: Department of Medicine, University of California San Diego, La Jolla, CA 92093
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