Retrovirus-like Gag Protein Arc1 Binds RNA and Traffics across Synaptic Boutons
Open accessAbstract
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.
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ARC possesses a Gag domain that is thought to have originated from a retrotransposon.
“The activity-regulated cytoskeleton-associated protein ARC, for example, possesses a Gag domain that is thought to have originated from a retrotransposon (Ashley et al. 2018, Pastuzyn et al. 2018).”
From The Role of Retrotransposons and Endogenous Retroviruses in Age-Dependent Neurodegenerative Disorders (2024) · cites this paper as Ashley et al. 2018
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Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2
Love, M. I., Huber, W., & Anders, S. (2014) · Genome Biology · doi:10.1186/s13059-014-0550-8 · Cited by 95,106 · see citing works
Ultrafast and memory-efficient alignment of short DNA sequences to the human genome.
Langmead, B., Trapnell, C., Pop, M., & Salzberg, S. L. (2009) · Genome Biology · doi:10.1186/gb-2009-10-3-r25 · Cited by 21,849 · see citing works
Streaming fragment assignment for real-time analysis of sequencing experiments
Roberts, A., & Pachter, L. (2013) · Nature Methods · doi:10.1038/nmeth.2251 · Cited by 1,063 · see citing works
Exosomes are released by cultured cortical neurones
Fauré, J., Lachenal, G., Court, M., Hirrlinger, J., Chatellard-Causse, C., Blot, B., Grange, J., Schoehn, G., Goldberg, Y., Boyer, V., et al. (2006) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2005.12.003 · Cited by 896 · see citing works
Alternative 3′ UTRs act as scaffolds to regulate membrane protein localization
Berkovits, B. D., & Mayr, C. (2015) · Nature · doi:10.1038/nature14321 · Cited by 474 · see citing works
Flagged first, then by citations
Research works printed but not linked: 49
- Abrusan G Szilagyi A Zhang Y Papp B 2013a Turning gold into ‘junk’: transposable elements utilize central proteins of cellular networks Nucleic Acids Res 41 3190 3200 doi:3110.1093/nar/gkt3011 Epub 2013 Jan 3121 23341038 PMC3597677 · DOI
- Abrusan G Szilagyi A Zhang Y Papp B 2013b Turning gold into ‘junk’: transposable elements utilize central proteins of cellular networks Nucleic Acids Res 41 3190 3200 23341038 PMC3597677
- Alenquer M Amorim MJ 2015 Exosome Biogenesis, Regulation, and Function in Viral Infection Viruses 7 5066 5083 doi:5010.3390/v7092862 26393640 PMC4584306 · DOI
- Alhowikan AM 2016 Activity-Regulated Cytoskeleton-Associated Protein Dysfunction May Contribute to Memory Disorder and Earlier Detection of Autism Spectrum Disorders Med Princ Pract 25 350 354 doi:310.1159/000445351 Epub 000442016 Mar 000445311 26967659 PMC5588424 · DOI
- Ataman B Ashley J Gorczyca D Gorczyca M Mathew D Wichmann C Sigrist SJ Budnik V 2006 Nuclear trafficking of Drosophila Frizzled-2 during synapse development requires the PDZ protein dGRIP Proc Natl Acad Sci U S A 103 7841 7846 16682643 PMC1472532
- Ataman B Ashley J Gorczyca M Ramachandran P Fouquet W Sigrist SJ Budnik V 2008 Rapid activity-dependent modifications in synaptic structure and function require bidirectional Wnt signaling Neuron 57 705 718 18341991 PMC2435264
- Basso M Bonetto V 2016 Extracellular Vesicles and a Novel Form of Communication in the Brain Front Neurosci 10 127 10.3389/fnins.2016.00127 eCollection 02016 27065789 PMC4814526 · DOI
- Budnik V 1996 Synapse maturation and structural plasticity at Drosophila neuromuscular junctions Curr Opin Neurobiol 6 858 867 9000022
- Budnik V Koh YH Guan B Hartmann B Hough C Woods D Gorczyca M 1996 Regulation of synapse structure and function by the Drosophila tumor suppressor gene dlg Neuron 17 627 640 8893021 PMC4661176
- Budnik V Zhong Y Wu CF 1990 Morphological plasticity of motor axons in Drosophila mutants with altered excitability J Neurosci 10 3754 3768 1700086 PMC6570094
- Campillos M Doerks T Shah PK Bork P 2006 Computational characterization of multiple Gag-like human proteins Trends Genet 22 585 589 Epub 2006 Sep 2018 16979784
- Cao C Rioult-Pedotti MS Migani P Yu CJ Tiwari R Parang K Spaller MR Goebel DJ Marshall J 2013 Impairment of TrkB-PSD-95 signaling in Angelman syndrome PLoS Biol 11 e1001478 23424281 PMC3570550
- Chen B 2016 HIV Capsid Assembly, Mechanism, and Structure Biochemistry 55 2539 2552 doi:2510.1021/acs.biochem.2536b00159 Epub 02016 Apr 00126 27074418 · DOI
- Chowdhury S Shepherd JD Okuno H Lyford G Petralia RS Plath N Kuhl D Huganir RL Worley PF 2006 Arc/Arg3.1 interacts with the endocytic machinery to regulate AMPA receptor trafficking Neuron 52 445 459 17088211 PMC1784006
- Comas-Garcia M Davis SR Rein A 2016 On the Selective Packaging of Genomic RNA by HIV-1 Viruses 8 PMC5035960 27626441
- Deutsch EW Csordas A Sun Z Jarnuczak A Perez-Riverol Y Ternent T Campbell DS Bernal-Llinares M Okuda S Kawano S 2017 The ProteomeXchange consortium in 2017: supporting the cultural change in proteomics public data deposition Nucleic Acids Res 45 D1100 D1106 27924013 PMC5210636
- Dynes JL Steward O 2007 Dynamics of bidirectional transport of Arc mRNA in neuronal dendrites J Comp Neurol 500 433 447 17120280
- Farris S Lewandowski G Cox CD Steward O 2014 Selective localization of arc mRNA in dendrites involves activity- and translation-dependent mRNA degradation J Neurosci 34 4481 4493 doi:4410.1523/JNEUROSCI.4944-4413.2014 24671994 PMC3965778 · DOI
- Fromer M Pocklington AJ Kavanagh DH Williams HJ Dwyer S Gormley P Georgieva L Rees E Palta P Ruderfer DM 2014 De novo mutations in schizophrenia implicate synaptic networks Nature 506 179 184 doi:110.1038/nature12929 Epub 12014 Jan 12922 24463507 PMC4237002 · DOI · Paper page
- Fruhbeis C Frohlich D Kuo WP Amphornrat J Thilemann S Saab AS Kirchhoff F Mobius W Goebbels S Nave KA 2013 Neurotransmitter-triggered transfer of exosomes mediates oligodendrocyte-neuron communication PLoS Biol 11 e1001604 doi:1001610.1001371/journal.pbio.1001604 Epub 1002013 Jul 1001609 23874151 PMC3706306 · DOI
- Gratz SJ Ukken FP Rubinstein CD Thiede G Donohue LK Cummings AM O’Connor-Giles KM 2014 Highly specific and efficient CRISPR/Cas9-catalyzed homology-directed repair in Drosophila Genetics 196 961 971 24478335 PMC3982687
- Harris KP Akbergenova Y Cho RW Baas-Thomas MS Littleton JT 2016 Shank Modulates Postsynaptic Wnt Signaling to Regulate Synaptic Development J Neurosci 36 5820 5832 doi:5810.1523/JNEUROSCI.4279-5815.2016 27225771 PMC4879199 · DOI
- Jan LY Jan YN 1982 Antibodies to horseradish peroxidase as specific neuronal markers in Drosophila and in grasshopper embryos Proc Natl Acad Sci U S A 79 2700 2704 6806816 PMC346269
- Kim D Pertea G Trapnell C Pimentel H Kelley R Salzberg SL 2013 TopHat2: accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions Genome Biol 14 R36 23618408 PMC4053844
- Koh YH Popova E Thomas U Griffith LC Budnik V 1999 Regulation of DLG localization at synapses by CaMKII-dependent phosphorylation Cell 98 353 363 10458610 PMC4656018
- Koles K Nunnari J Korkut C Barria R Brewer C Li Y Leszyk J Zhang B Budnik V 2012 Mechanism of evenness interrupted (Evi)-exosome release at synaptic boutons J Biol Chem 287 16820 16834 22437826 PMC3351299
- Koon AC Ashley J Barria R DasGupta S Brain R Waddell S Alkema MJ Budnik V 2011 Autoregulatory and paracrine control of synaptic and behavioral plasticity by octopaminergic signaling Nat Neurosci 14 190 199 21186359 PMC3391700
- Korkut C Ataman B Ramachandran P Ashley J Barria R Gherbesi N Budnik V 2009 Trans-synaptic transmission of vesicular Wnt signals through Evi/Wntless Cell 139 393 404 19837038 PMC2785045
- Korkut C Li Y Koles K Brewer C Ashley J Yoshihara M Budnik V 2013 Regulation of postsynaptic retrograde signaling by presynaptic exosome release Neuron 77 1039 1039 23522040 PMC3626103
- Lander ES Linton LM Birren B Nusbaum C Zody MC Baldwin J Devon K Dewar K Doyle M FitzHugh W 2001 Initial sequencing and analysis of the human genome Nature 409 860 921 11237011
- Lefebvre FA Benoit Bouvrette LP Perras L Blanchet-Cohen A Garnier D Rak J Lecuyer E 2016 Comparative transcriptomic analysis of human and Drosophila extracellular vesicles Sci Rep 6 27680 10.1038/srep27680 27282340 PMC4901365 · DOI
- Lyford GL Yamagata K Kaufmann WE Barnes CA Sanders LK Copeland NG Gilbert DJ Jenkins NA Lanahan AA Worley PF 1995 Arc, a growth factor and activity-regulated gene, encodes a novel cytoskeleton-associated protein that is enriched in neuronal dendrites Neuron 14 433 445 7857651
- Mattaliano MD Montana ES Parisky KM Littleton JT Griffith LC 2007 The Drosophila ARC homolog regulates behavioral responses to starvation Molecular and cellular neurosciences 36 211 221 17707655 PMC2094000
- Meckes DG Jr 2015 Exosomal communication goes viral J Virol 89 5200 5203 25740980 PMC4442506
- Myrum C Baumann A Bustad HJ Flydal MI Mariaule V Alvira S Cuellar J Haavik J Soule J Valpuesta JM 2015 Arc is a flexible modular protein capable of reversible self-oligomerization Biochem J 468 145 158 25748042 PMC4422259
- Nallamsetty S Austin BP Penrose KJ Waugh DS 2005 Gateway vectors for the production of combinatorially-tagged His6-MBP fusion proteins in the cytoplasm and periplasm of Escherichia coli Protein Sci 14 2964 2971 16322578 PMC2253240
- Nefedova L Kim A 2017 Mechanisms of LTR-Retroelement Transposition: Lessons from Drosophila melanogaster Viruses 9 PMC5408687 28420154
- Nishida KM Miyoshi K Ogino A Miyoshi T Siomi H Siomi MC 2013 Roles of R2D2, a cytoplasmic D2 body component, in the endogenous siRNA pathway in Drosophila Mol Cell 49 680 691 23375501
- Peebles CL Yoo J Thwin MT Palop JJ Noebels JL Finkbeiner S 2010 Arc regulates spine morphology and maintains network stability in vivo Proc Natl Acad Sci U S A 107 18173 18178 doi:18110.11073/pnas.1006546107 Epub 1006542010 Oct 1006546104 20921410 PMC2964216 · DOI
- Port F Bullock SL 2016 Creating Heritable Mutations in Drosophila with CRISPR-Cas9 Methods Mol Biol 1478 145 160 27730579
- Satoh AK O’Tousa JE Ozaki K Ready DF 2005 Rab11 mediates post-Golgi trafficking of rhodopsin to the photosensitive apical membrane of Drosophila photoreceptors Development 132 1487 1497 15728675
- Schneider I 1972 Cell lines derived from late embryonic stages of Drosophila melanogaster J Embryol Exp Morphol 27 353 365 4625067
- Shepherd JD Bear MF 2011 New views of Arc, a master regulator of synaptic plasticity Nat Neurosci 14 279 284 doi:210.1038/nn.2708 Epub 2011 Jan 1030 21278731 PMC8040377 · DOI · Paper page
- Speese SD Ashley J Jokhi V Nunnari J Barria R Li Y Ataman B Koon A Chang YT Li Q 2012 Nuclear envelope budding enables large ribonucleoprotein particle export during synaptic Wnt signaling Cell 149 832 846 22579286 PMC3371233
- Stewart BA Atwood HL Renger JJ Wang J Wu CF 1994 Improved stability of Drosophila larval neuromuscular preparations in haemolymph-like physiological solutions J Comp Physiol A 175 179 191 8071894
- Trapnell C Roberts A Goff L Pertea G Kim D Kelley DR Pimentel H Salzberg SL Rinn JL Pachter L 2012 Differential gene and transcript expression analysis of RNA-seq experiments with TopHat and Cufflinks Nat Protoc 7 562 578 22383036 PMC3334321
- Viola H Ballarini F Martinez MC Moncada D 2014 The tagging and capture hypothesis from synapse to memory Prog Mol Biol Transl Sci 122 391 423 10.1016/B1978-1010-1012-420170-420175.400013-420171 24484708 · DOI
- Vizcaino JA Csordas A del-Toro N Dianes JA Griss J Lavidas I Mayer G Perez-Riverol Y Reisinger F Ternent T 2016 2016 update of the PRIDE database and its related tools Nucleic Acids Res 44 D447 456 26527722 PMC4702828
- Zhang W Wu J Ward MD Yang S Chuang YA Xiao M Li R Leahy DJ Worley PF 2015 Structural basis of arc binding to synaptic proteins: implications for cognitive disease Neuron 86 490 500 doi:410.1016/j.neuron.2015.1003.1030 Epub 2015 Apr 1019 25864631 PMC4409568 · DOI
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- Authors
- Ashley, J., Cordy, B., Lucia, D., Fradkin, L. G., Budnik, V., & Thomson, T.
- Affiliations
- University of Massachusetts Chan Medical School (US)
- Corresponding author
- Budnik, Vivian
- Thomson, Travis
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2018-01
- Volume
- 172
- Issue
- 1-2
- Pages
- 262-274.e11
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC5793882
- OpenAlex
- W2783435551
- Cited by
- 488
- References
- 5
- Citations by year
- 2026: 32 · 2025: 53 · 2024: 77 · 2023: 48 · 2022: 50 · 2021: 63 · 2020: 56 · 2019: 60 · 2018: 48
- FWCI
- 20.19
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- The Journal of the American Medical Association (JAMA) Network (American Medical Association) (submittedVersion)
- Funders
- NIH (P40OD018537, R37MH070000)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Keywords
- Arc/Arg3.1, ARC1, retrotransposons, copia, extracellular vesicles, mRNA transport, synaptic plasticity, synaptic boutons, 3' untranslated region, Drosophila, autism spectrum disorder, schizophrenia
- MeSH terms
- Protein Domains, Animals, Biological Transport, Cells, Cultured, Cytoskeletal Proteins, Drosophila, Nerve Tissue Proteins, Neuromuscular Junction, Neuronal Plasticity, Peptide Hydrolases, Protein Binding, RNA, Messenger, Gene Products, gag, Presynaptic Terminals, Retroelements, Drosophila Proteins, Multivesicular Bodies
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