RESUMEN
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.
Asunto(s)
Proteínas del Citoesqueleto/metabolismo , Exosomas/metabolismo , Productos del Gen gag/genética , Proteínas del Tejido Nervioso/metabolismo , Neuronas/metabolismo , ARN Mensajero/metabolismo , Animales , Células Cultivadas , Proteínas del Citoesqueleto/química , Proteínas del Citoesqueleto/genética , Endocitosis , Femenino , Productos del Gen gag/química , Células HEK293 , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Proteínas del Tejido Nervioso/química , Proteínas del Tejido Nervioso/genética , Neuronas/fisiologíaRESUMEN
Viruses and transposable elements are major drivers of evolution and make up over half the sequences in the human genome. In some cases, these elements are co-opted to perform biological functions for the host. Recent studies made the surprising observation that the neuronal gene Arc forms virus-like protein capsids that can transfer RNA between neurons to mediate a novel intercellular communication pathway. Phylogenetic analyses showed that mammalian Arc is derived from an ancient retrotransposon of the Ty3/gypsy family and contains homology to the retroviral Gag polyproteins. The Drosophila Arc homologs, which are independently derived from the same family of retrotransposons, also mediate cell-to-cell signaling of RNA at the neuromuscular junction; a striking example of convergent evolution. Here we propose an Arc 'life cycle', based on what is known about retroviral Gag, and discuss how elucidating these biological processes may lead to novel insights into brain plasticity and memory.