Department of Neurobiology and Anatomy, The University of Utah, Salt Lake City, UT, USA.
Department of Human Genetics, The University of Utah, Salt Lake City, UT, USA.
Cell. 2018 Jan 11;172(1-2):275-288.e18. doi: 10.1016/j.cell.2017.12.024.
The neuronal gene Arc is essential for long-lasting information storage in the mammalian brain, mediates various forms of synaptic plasticity, and has been implicated in neurodevelopmental disorders. However, little is known about Arc's molecular function and evolutionary origins. Here, we show that Arc self-assembles into virus-like capsids that encapsulate RNA. Endogenous Arc protein is released from neurons in extracellular vesicles that mediate the transfer of Arc mRNA into new target cells, where it can undergo activity-dependent translation. Purified Arc capsids are endocytosed and are able to transfer Arc mRNA into the cytoplasm of neurons. These results show that Arc exhibits similar molecular properties to retroviral Gag proteins. Evolutionary analysis indicates that Arc is derived from a vertebrate lineage of Ty3/gypsy retrotransposons, which are also ancestors to retroviruses. These findings suggest that Gag retroelements have been repurposed during evolution to mediate intercellular communication in the nervous system.
神经元基因 Arc 对于哺乳动物大脑中的长期信息存储至关重要，介导各种形式的突触可塑性，并与神经发育障碍有关。然而，Arc 的分子功能和进化起源知之甚少。在这里，我们表明 Arc 自我组装成类似病毒的衣壳，将 RNA 包裹在内。内源性 Arc 蛋白从神经元中以细胞外囊泡的形式释放出来，介导 Arc mRNA 转移到新的靶细胞中，在靶细胞中，Arc mRNA 可以进行活性依赖性翻译。纯化的 Arc 衣壳被内吞，并能够将 Arc mRNA 转移到神经元的细胞质中。这些结果表明 Arc 表现出与逆转录病毒 Gag 蛋白相似的分子特性。进化分析表明，Arc 源自脊椎动物 Ty3/gypsy 逆转录转座子的谱系，逆转录转座子也是逆转录病毒的祖先。这些发现表明，Gag 逆转录元件在进化过程中被重新利用，以介导神经系统中的细胞间通讯。
