CEP290 interacts with the centriolar satellite component PCM-1 and is required for Rab8 localization to the primary cilium
CEP290 interacts with the centriolar satellite component PCM-1 and is required for Rab8 localization to the primary cilium
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DOI：
10.1093/hmg/ddn277
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发表时间：
2008-12-01
影响因子：
3.5
通讯作者：
Gleeson, Joseph G.
中科院分区：
文献类型：
--
作者：
Kim, Joon;Krishnaswami, Suguna Rani;Gleeson, Joseph G.
Joubert综合征(JS)是一种以小脑蠕虫发育不全、眼球运动异常、共济失调和智力低下为特征的发育性脑疾病。CEP290突变是JS的小脑-眼-肾亚型的原因，包括肾囊肿和视网膜变性，这两种表型通常与纤毛疾病有关。CEP290突变还与Meckel-Gruber综合征和Bardet-Biedl综合征(BBS)相关。在这里，我们证明了CEP290与中心粒卫星蛋白PCM-1相互作用，这与BBS4的功能有关。CEP290与PCM-1结合，并以PCM-1和微管依赖的方式定位于中心粒卫星。CEP290的缺失扰乱了PCM-1的亚细胞分布和蛋白质复合体的形成。与PCM-1的S在微管组织中的作用一致，CEP290基因被敲除后导致细胞质微管网络的解体。此外，我们发现CEP290和PCM-1都是纤毛发生所必需的，并参与了Rab8的纤毛靶向，Rab8是一种小的GTP酶，被证明与BBS蛋白复合体合作促进纤毛发生。我们的结果表明，PCM-1可能是一个潜在的介体，可能在共同的分子途径中将CEP290与BBS蛋白联系起来。
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.