Department of Cell Biology and Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA.
Laboratory for Therapeutic Development, Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, QC H3G 1Y6, Canada.
Cell. 2014 Jul 17;158(2):368-382. doi: 10.1016/j.cell.2014.05.042.
Adenomatous polyposis coli (APC) is a microtubule plus-end scaffolding protein important in biology and disease. APC is implicated in RNA localization, although the mechanisms and functional significance remain unclear. We show APC is an RNA-binding protein and identify an RNA interactome by HITS-CLIP. Targets were highly enriched for APC-related functions, including microtubule organization, cell motility, cancer, and neurologic disease. Among the targets is β2B-tubulin, known to be required in human neuron and axon migration. We show β2B-tubulin is synthesized in axons and localizes preferentially to dynamic microtubules in the growth cone periphery. APC binds the β2B-tubulin 3' UTR; experiments interfering with this interaction reduced β2B-tubulin mRNA axonal localization and expression, depleted dynamic microtubules and the growth cone periphery, and impaired neuron migration. These results identify APC as a platform binding functionally related protein and RNA networks, and suggest a self-organizing model for the microtubule to localize synthesis of its own subunits.
腺瘤性结肠息肉病（APC）是一种微管正端支架蛋白，在生物学和疾病中具有重要作用。APC 参与 RNA 定位，但其机制和功能意义尚不清楚。我们发现 APC 是一种 RNA 结合蛋白，并通过 HITS-CLIP 鉴定了一个 RNA 相互作用组。靶标高度富集与 APC 相关的功能，包括微管组织、细胞运动、癌症和神经疾病。其中的靶标是β2B-微管蛋白，已知其在人类神经元和轴突迁移中是必需的。我们发现β2B-微管蛋白在轴突中合成，并优先定位于生长锥外围的动态微管上。APC 结合β2B-微管蛋白 3'UTR；干扰这种相互作用的实验减少了β2B-微管蛋白 mRNA 在轴突中的定位和表达，耗尽了动态微管和生长锥外围，并损害了神经元迁移。这些结果表明 APC 作为一个平台，结合功能相关的蛋白质和 RNA 网络，并提出了一个微管定位其自身亚基合成的自组织模型。
