Kim Joon, Krishnaswami Suguna Rani, Gleeson Joseph G
Department of Neurosciences, Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA 92093, USA.
Hum Mol Genet. 2008 Dec 1;17(23):3796-805. doi: 10.1093/hmg/ddn277. Epub 2008 Sep 4.
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.
乔布综合征（JS）是一种发育性脑疾病，其特征为小脑蚓部发育不全、眼球运动异常、共济失调和智力发育迟缓。CEP290基因突变导致JS的脑-眼-肾亚型，该亚型包括肾囊肿和视网膜变性，这两种表型通常与纤毛病相关。CEP290基因突变还与梅克尔-格鲁伯综合征和巴德-比德尔综合征（BBS）有关。在此，我们证明CEP290与一种中心粒卫星蛋白PCM-1相互作用，PCM-1与BBS4功能有关。CEP290与PCM-1结合，并以依赖于PCM-1和微管的方式定位于中心粒卫星。CEP290的缺失会破坏PCM-1的亚细胞分布和蛋白质复合物形成。与PCM-1在微管组织中的作用一致，CEP290基因敲低会导致细胞质微管网络紊乱。此外，我们表明CEP290和PCM-1都是纤毛发生所必需的，并且参与Rab8的纤毛靶向，Rab8是一种小GTP酶，已证明其与BBS蛋白质复合物协同促进纤毛发生。我们的结果表明，PCM-1可能是一种潜在的介质，在共同的分子途径中连接CEP290和BBS蛋白。
