FGFR1-mediated protocadherin-15 loading mediates cargo specificity during intraflagellar transport in inner ear hair-cell kinocilia
FGFR1-mediated protocadherin-15 loading mediates cargo specificity during intraflagellar transport in inner ear hair-cell kinocilia
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DOI：
10.1073/pnas.1719861115
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发表时间：
2018-08-14
影响因子：
11.1
通讯作者：
Ladher, Raj K.
中科院分区：
文献类型：
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作者：
Honda, Akira;Kita, Tomoko;Ladher, Raj K.
内耳的机械感觉毛细胞是听觉和平衡所必需的，并且具有独特的顶端结构，即毛束，其将机械刺激转化为电信号。这种结构包括一个单一的纤毛，动纤毛，躺在附近的一个合奏肌动蛋白为基础的预测称为静纤毛。毛束极性取决于动纤毛原钙粘蛋白15（Pcdh 15）的定位。原钙粘蛋白-15只存在于毛细胞动纤毛中，并不局限于相邻支持细胞的初级纤毛。因此，Pcdh 15必须被特异性地靶向并贩运到毛细胞动纤毛中。在这里，我们表明，动纤毛Pcdh 15贩运依赖于细胞类型特异性耦合到通用的鞭毛内运输（IFT）运输机制。我们发现成纤维细胞生长因子受体1（FGFR 1）在加载Pcdh 15到毛细胞中的动纤毛运输颗粒的作用。我们发现，在激活时，FGFR 1结合并磷酸化Pcdh 15。此外，我们发现了一个以前未表征的作用网格蛋白在耦合这kinocilia特定的货物与顺行IFT-B复合物通过适配器，DAB 2。我们的研究结果确定了一个修改后的纤毛运输途径用于Pcdh 15运输到纤毛的内耳毛细胞和协调FGFR 1活性。
The mechanosensory hair cells of the inner ear are required for hearing and balance and have a distinctive apical structure, the hair bundle, that converts mechanical stimuli into electrical signals. This structure comprises a single cilium, the kinocilium, lying adjacent to an ensemble of actin-based projections known as stereocilia. Hair bundle polarity depends on kinociliary protocadherin-15 (Pcdh15) localization. Protocadherin-15 is found only in hair-cell kinocilia, and is not localized to the primary cilia of adjacent supporting cells. Thus, Pcdh15 must be specifically targeted and trafficked into the hair-cell kinocilium. Here we show that kinocilial Pcdh15 trafficking relies on cell type-specific coupling to the generic intraflagellar transport (IFT) transport mechanism. We uncover a role for fibroblast growth factor receptor 1 (FGFR1) in loading Pcdh15 onto kinociliary transport particles in hair cells. We find that on activation, FGFR1 binds and phosphorylates Pcdh15. Moreover, we find a previously uncharacterized role for clathrin in coupling this kinocilia-specific cargo with the anterograde IFT-B complex through the adaptor, DAB2. Our results identify a modified ciliary transport pathway used for Pcdh15 transport into the cilium of the inner ear hair cell and coordinated by FGFR1 activity.