PDF(Pubmed)
Abstract：
The first steps of vision take place in the ciliary outer segment compartment of photoreceptor cells. The protein composition of outer segments is uniquely suited to perform this function. The most abundant among these proteins is the visual pigment, rhodopsin, whose outer segment trafficking involves intraflagellar transport (IFT). Here, we report three major findings from the analysis of mice in which ciliary transport was acutely impaired by conditional knockouts of IFT-B subunits. First, we demonstrate the existence of a sorting mechanism whereby mislocalized rhodopsin is recruited to and concentrated in extracellular vesicles prior to their release, presumably to protect the cell from adverse effects of protein mislocalization. Second, reducing rhodopsin expression significantly delays photoreceptor degeneration caused by IFT disruption, suggesting that controlling rhodopsin levels may be an effective therapy for some cases of retinal degenerative disease. Last, the loss of IFT-B subunits does not recapitulate a phenotype observed in mutants of the BBSome (another ciliary transport protein complex relying on IFT) in which non-ciliary proteins accumulate in the outer segment. Whereas it is widely thought that the role of the BBSome is to primarily participate in ciliary transport, our data suggest that the BBSome has another major function independent of IFT and possibly related to maintaining the diffusion barrier of the ciliary transition zone.
摘要：
视觉的第一步发生在感光细胞的睫状外段隔室中。外节段的蛋白质组成独特地适合于执行该功能。这些蛋白质中最丰富的是视觉色素，视紫红质,其外段贩运涉及滑膜内运输(IFT)。这里,我们报告了对小鼠的分析的三个主要发现，其中有条件的IFT-B亚基敲除会严重损害纤毛运输。首先,我们证明了一种分选机制的存在，其中错误定位的视紫红质在释放之前被募集并集中在细胞外囊泡中，可能是为了保护细胞免受蛋白质错位的不利影响。第二,减少视紫红质的表达显着延迟由IFT破坏引起的光感受器变性，提示控制视紫红质水平可能是一些视网膜退行性疾病的有效治疗方法。最后,IFT-B亚基的丢失并不能概括在BBSome（另一种依赖IFT的纤毛转运蛋白复合物）突变体中观察到的表型，其中非纤毛蛋白在外部片段中积累。尽管人们普遍认为BBSome的作用主要是参与纤毛运输，我们的数据表明，BBSome具有另一个独立于IFT的主要功能，可能与维持睫状过渡区的扩散屏障有关。
