Late Endosomes Act as mRNA Translation Platforms and Sustain Mitochondria in Axons
Late Endosomes Act as mRNA Translation Platforms and Sustain Mitochondria in Axons
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DOI：
10.1016/j.cell.2018.11.030
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发表时间：
2019-01-10
期刊：
影响因子：
64.5
通讯作者：
Holt, Christine E.
中科院分区：
文献类型：
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作者：
Cioni, Jean-Michel;Lin, Julie Qiaojin;Holt, Christine E.
局部翻译调节轴突蛋白质组，在神经元布线和轴突维持中起重要作用。然而，轴突mRNA如何定位于特定的亚细胞位点进行翻译尚不清楚。在这里，我们报告说，RNA颗粒与内体沿着轴突的视网膜神经节细胞。Rab 7a晚期内体也与核糖体结合，实时翻译成像显示它们是局部蛋白质合成的位点。我们表明，携带RNA的晚期内体经常在线粒体上暂停，并且编码线粒体功能蛋白质的mRNA在Rab 7a内体上翻译。Rab 7a突变体（包括与Charcot-Marie-Tooth 2B型神经病相关的突变体）对Rab 7a功能的破坏显著降低轴突蛋白合成，损害线粒体功能，并损害轴突活力。因此，我们的研究结果表明，晚期内体与RNA颗粒，翻译机器和线粒体相互作用，并表明它们作为调节轴突中新生促生存蛋白供应的位点。
Local translation regulates the axonal proteome, playing an important role in neuronal wiring and axon maintenance. How axonal mRNAs are localized to specific subcellular sites for translation, however, is not understood. Here we report that RNA granules associate with endosomes along the axons of retinal ganglion cells. RNA-bearing Rab7a late endosomes also associate with ribosomes, and real-time translation imaging reveals that they are sites of local protein synthesis. We show that RNA-bearing late endosomes often pause on mitochondria and that mRNAs encoding proteins for mitochondrial function are translated on Rab7a endosomes. Disruption of Rab7a function with Rab7a mutants, including those associated with Charcot-Marie-Tooth type 2B neuropathy, markedly decreases axonal protein synthesis, impairs mitochondrial function, and compromises axonal viability. Our findings thus reveal that late endosomes interact with RNA granules, translation machinery, and mitochondria and suggest that they serve as sites for regulating the supply of nascent pro-survival proteins in axons.