Retrovirus-like Gag Protein Arc1 Binds RNA and Traffics across Synaptic Boutons

Abstract

Arc/Arg3.1 is required for synaptic plasticity and cognition, and mutations in this gene are linked to autism and schizophrenia. Arc bears a domain resembling retroviral/retrotransposon Gag-like proteins, which multimerize into a capsid that packages viral RNA. The significance of such a domain in a plasticity molecule is uncertain. Here, we report that the Drosophila Arc1 protein forms capsid-like structures that bind darc1 mRNA in neurons and is loaded into extracellular vesicles that are transferred from motorneurons to muscles. This loading and transfer depends on the darc1-mRNA 3' untranslated region, which contains retrotransposon-like sequences. Disrupting transfer blocks synaptic plasticity, suggesting that transfer of dArc1 complexed with its mRNA is required for this function. Notably, cultured cells also release extracellular vesicles containing the Gag region of the Copia retrotransposon complexed with its own mRNA. Taken together, our results point to a trans-synaptic mRNA transport mechanism involving retrovirus-like capsids and extracellular vesicles.

The Neuronal Gene Arc Encodes a Repurposed Retrotransposon Gag Protein that Mediates Intercellular RNA Transfer

“…Our study is complementary to Ashley et al (2018), published in the same issue of Cell , in showing the homology between Arc and Gag proteins and revealing a new signaling pathway in neurons. We have added a citation to this paper in the Introduction.…”

Plasticity of Spine Structure: Local Signaling, Translation and Cytoskeletal Reorganization

“…Arc and viral Gag share key functional features such as membrane binding (Barylko et al, 2018), self-oligomerization of capsid-like protein (Myrum et al, 2015; Ashley et al, 2018; Pastuzyn et al, 2018), RNA-binding and EV-mediated exosomal releases (Ashley et al, 2018; Pastuzyn et al, 2018; Shepherd, 2018). It is still elusive whether other proteins and mRNAs can be also transferred between neurons through similar mechanisms.…”

Initiated by CREB: Resolving Gene Regulatory Programs in Learning and Memory

“…However, ARC might have another role during plasticity. ARC has viral group‐specific antigen (Gag) polyprotein elements and with these GAG elements, ARC is able to form capsids . These capsids can then be exocytosed in exosomes (Figure ), which is a communication method between neurons and between neurons and glia .…”

“…These capsids can then be exocytosed in exosomes (Figure ), which is a communication method between neurons and between neurons and glia . Most interestingly, the ARC capsids contain ARC RNA but they are also able to encapsidate other mRNAs . In the Drosophila neuromuscular junction, the trans‐synaptic transport of ARC is required for synaptic plasticity .…”