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

Pastuzyn, Elissa D.; Day, Cameron E.; Kearns, Rachel B.; Kyrke-Smith, Madeleine; Taibi, Andrew; McCormick, John; Yoder, Nathan; Belnap, David M.; Erlendsson, Simon; Morado, Dustin R.; Briggs, John; Feschotte, Cédric; Shepherd, Jason D.

doi:10.1016/j.cell.2018.03.024

Cited by 210 publications

(330 citation statements)

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“…Here, using PBS buffer in sample preparation, we show that wild-type human Arc forms rounded, viral-like capsids (Fig. 6) similar in size and shape to those reported for recombinant rat and Drosophila Arc (Ashley et al, 2018;Pastuzyn et al, 2018). The majority of capsids have a diameter of ~30 nm, although there is heterogeneity in size.…”

Section: The Ntd Second Coil Motif Mediates Formation Of Arc Capsidssupporting

confidence: 78%

Section: Introductionmentioning

confidence: 99%

“…Remarkably, recombinant Arc from fruit fly and rat was subsequently shown to self-assemble into spheroid particles with resemblance to HIV Gag capsids (Ashley et al, 2018;Pastuzyn et al, 2018). The Arc capsids are released in extracellular vesicles and capable of transmitting RNA cargo to recipient cells (Ashley et al, 2018;Pastuzyn et al, 2018). These discoveries implicate Arc as an endogenous neuronal retrovirus, and oligomeric assembly of Arc into virus-like capsids mediates the capture and intercellular transfer of RNA (Parrish and Tomonaga, 2018;Shepherd, 2018).…”

Section: Introductionmentioning

confidence: 99%

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Molecular determinants of Arc oligomerization and formation of virus-like capsids

Eriksen

Nikolaienko

Hallin

et al. 2019

Preprint

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Expression of activity-regulated cytoskeleton-associated protein (Arc) is critical for long-term synaptic plasticity, memory formation, and cognitive flexibility. The ability of Arc to self-associate and form virus-like capsid structures implies functionally distinct oligomeric states. However, the molecular mechanism of Arc oligomerization is unknown. Here, we identified a 28-amino-acid region necessary and sufficient for Arc oligomerization. This oligomerization region is located within the second coil of a predicted anti-parallel coiled-coil in the N-terminal domain (NTD). Using alanine scanning mutagenesis, we found a 7-amino-acid motif critical for oligomerization and Arc-mediated transferrin endocytosis in HEK cells. Intermolecular fluorescence lifetime imaging in hippocampal neurons confirmed selfassociation mediated by the motif. To quantify oligomeric size, we performed a single-molecule photobleaching analysis of purified Arc wild-type and mutant. This analysis revealed a critical role for the NTD motif in the formation of higher-order Arc oligomers (30-170 molecules). Moreover, assembly of higher-order wild-type Arc oligomers was significantly enhanced by addition of GFP RNA. Purified wild-type Arc formed virus-like capsids, as visualized by negative-stain EM, and was estimated by light scattering analysis to contain 40-55 Arc units. In contrast, mutant Arc formed a homogenous dimer population as demonstrated by single-molecule TIRF imaging, size-exclusion chromatography with multi-angle light scattering analysis, small-angle X-ray scattering analysis, and single-particle 3D EM reconstruction. Thus, the dimer appears to be the basic building block for assembly. Herein, we show that the NTD motif is essential for higher-order Arc oligomerization, assembly of virus-like capsid particles, and facilitation of oligomerization by exogenous RNA. SIGNIFICANCEArc protein is rapidly expressed in neurons in response to synaptic activity and plays critical roles in synaptic plasticity, postnatal cortical developmental, and memory. Arc has diverse molecular functions, which may be related to distinct oligomeric states of the protein. Arc has homology to retroviral Gag protein and self-assembles into retrovirus-like capsid structures that are capable of intercellular transfer of RNA. Here, we identified a motif in the N-terminal coiled-coil domain of mammalian Arc that mediates higher-order oligomerization and formation of virus-like capsids. The basic building block is the Arc dimer and exogenous RNA facilitates further assembly. The identified molecular determinants of Arc oligomerization will help to elucidate the functional modalities of Arc in the mammalian brain. Recent advances highlight a structural and functional relationship between Arc and retroviralGag polyprotein. Arc was identified in a computational search for domesticated retrotransposons harboring Gag-like protein domains (Campillos et al., 2006). Biochemical studies showed that mammalian Arc has a positively charged N-terminal domain (NTD) and a ne...

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Section: The Ntd Second Coil Motif Mediates Formation Of Arc Capsidssupporting

confidence: 78%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Molecular determinants of Arc oligomerization and formation of virus-like capsids

Eriksen

Nikolaienko

Hallin

et al. 2019

Preprint

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“…Other studies associated rare Arc gene mutations with mental disorders in humans, including schizophrenia [2]. Then in January 2018, two papers confirmed that the Arc protein assembles itself into virus-like capsids that bind mRNA and transfer it to target cells [3,4]. "At the moment we argue by analogy and say this must be able to assemble, must be like a retrovirus, but we do not know in which ways it is like a retrovirus and which it is not. "…”

Section: Learning and Memorymentioning

confidence: 99%

Ancient foes and helpers

Hunter¹

2019

EMBO Reports

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“…Persistence may be reached from fully functional viruses that have exapted old functional motifs for new traitssuch as in the syncytin genes or the neuronal arc genes-to viral defectives, such as the great variety of transposable elements and other noncoding RNAs, all of which can be identified as repetitive sequence structures in either RNA or DNA. [170][171][172][173][174] Without a doubt, transposable elements represent key agents to change genome identities for various adaptive purposes in a rather flexible and module-based, and even social, manner. But this inherent capability to change genome integrity and sequence order with far-reaching consequences for the adaptability of the host organisms must be restricted to ensure an acceptable level of genome integrity (e.g., genome immunity).…”

Section: Disease: Dysfunctional Communicationmentioning

confidence: 99%

That is life: communicating RNA networks from viruses and cells in continuous interaction

Villarreal

Witzany²

2019

Annals of the New York Academy of Sciences

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All the conserved detailed results of evolution stored in DNA must be read, transcribed, and translated via an RNA‐mediated process. This is required for the development and growth of each individual cell. Thus, all known living organisms fundamentally depend on these RNA‐mediated processes. In most cases, they are interconnected with other RNAs and their associated protein complexes and function in a strictly coordinated hierarchy of temporal and spatial steps (i.e., an RNA network). Clearly, all cellular life as we know it could not function without these key agents of DNA replication, namely rRNA, tRNA, and mRNA. Thus, any definition of life that lacks RNA functions and their networks misses an essential requirement for RNA agents that inherently regulate and coordinate (communicate to) cells, tissues, organs, and organisms. The precellular evolution of RNAs occurred at the core of the emergence of cellular life and the question remained of how both precellular and cellular levels are interconnected historically and functionally. RNA networks and RNA communication can interconnect these levels. With the reemergence of virology in evolution, it became clear that communicating viruses and subviral infectious genetic parasites are bridging these two levels by invading, integrating, coadapting, exapting, and recombining constituent parts in host genomes for cellular requirements in gene regulation and coordination aims. Therefore, a 21st century understanding of life is of an inherently social process based on communicating RNA networks, in which viruses and cells continuously interact.

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

Cited by 210 publications

References 2 publications

Molecular determinants of Arc oligomerization and formation of virus-like capsids

Molecular determinants of Arc oligomerization and formation of virus-like capsids

Ancient foes and helpers

That is life: communicating RNA networks from viruses and cells in continuous interaction

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