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Human Molecular Genetics Advance Access originally published online on September 4, 2008
Human Molecular Genetics 2008 17(23):3796-3805; doi:10.1093/hmg/ddn277
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

CEP290 interacts with the centriolar satellite component PCM-1 and is required for Rab8 localization to the primary cilium

Joon Kim1, Suguna Rani Krishnaswami1,{dagger} and Joseph G. Gleeson1,*

1 Department of Neurosciences, Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA 92093, USA

* 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, USA. Tel: +1 8588223535; Fax: +1 8588221021; Email: jogleeson{at}ucsd.edu

Received May 30, 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 mutations are responsible for the cerebello–oculo–renal subtype of JS that includes kidney cysts and retinal degeneration, two phenotypes commonly linked to ciliopathies. CEP290 mutations are also associated with Meckel–Gruber syndrome 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. The 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 the 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.

{dagger} Present address: Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA.


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