Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor,Michigan 48105, USA.
J Biol Chem. 2011 Aug 12;286(32):28276-86. doi: 10.1074/jbc.M111.237560. Epub 2011 Jun 17.
Primary cilia regulate polarized protein trafficking in photoreceptors, which are dynamic and highly compartmentalized sensory neurons of retina. The ciliary protein Cep290 modulates cilia formation and is frequently mutated in syndromic and non-syndromic photoreceptor degeneration. However, the underlying mechanism of associated retinopathy is unclear. Using the Cep290 mutant mouse rd16 (retinal degeneration 16), we show that Cep290-mediated photoreceptor degeneration is associated with aberrant accumulation of its novel interacting partner Rkip (Raf-1 kinase inhibitory protein). This effect is phenocopied by morpholino-mediated depletion of cep290 in zebrafish. We further demonstrate that ectopic accumulation of Rkip leads to defective cilia formation in zebrafish and cultured cells, an effect mediated by its interaction with the ciliary GTPase Rab8A. Our data suggest that Rkip prevents cilia formation and is associated with Cep290-mediated photoreceptor degeneration. Furthermore, our results indicate that preventing accumulation of Rkip could potentially ameliorate such degeneration.
初级纤毛调节感光细胞中的极化蛋白运输，感光细胞是视网膜中动态且高度分隔的感觉神经元。纤毛蛋白 Cep290 调节纤毛形成，并且在综合征和非综合征感光细胞变性中经常发生突变。然而，相关视网膜病变的潜在机制尚不清楚。使用 Cep290 突变小鼠 rd16（视网膜变性 16），我们表明 Cep290 介导的感光细胞变性与它的新型相互作用伙伴 Rkip（Raf-1 激酶抑制蛋白）的异常积累有关。这种效应可以通过在斑马鱼中用 morpholino 介导的 cep290 耗竭来模拟。我们进一步证明，Rkip 的异位积累导致斑马鱼和培养细胞中的纤毛形成缺陷，这种效应是由其与纤毛 GTPase Rab8A 的相互作用介导的。我们的数据表明，Rkip 阻止纤毛形成，并与 Cep290 介导的感光细胞变性有关。此外，我们的结果表明，防止 Rkip 的积累可能潜在地改善这种变性。
