A Syd and RUFY dynein adaptor complex mediates axonal circulation of dense core vesicles
Open accessPublished version of a preprint
Abstract
Neuropeptide-containing dense core vesicles (DCVs) generated in neuronal somata are circulated in axons to supply distal release sites, depending on kinesin-1, kinesin-3, and dynein, but how the motors are recruited remains unclear. Here we use proximity proteomics in the living Drosophila nervous system to identify the protein complex responsible for recruitment of kinesin-1 and dynein on DCVs. We find that the dynein and kinesin-1 adaptor Sunday driver (Syd/dJIP3/4) interact with the DCV-located GTPase Rab2 and also bind the Arl8 effector RUFY. Disrupting Rab2, Syd, RUFY, the Arl8 activator BORC, or dynein impedes retrograde DCV flux and induces axonal accumulation of immobile DCVs. Our data suggest that dynein is recruited and activated by a Syd/RUFY complex anchored to DCVs by Rab2 and Arl8. Rab2 loss but not disruption of Syd, RUFY, or dynein causes missorting of DCV membrane proteins into vesicle aggregates in motor neuron somata, suggesting that Rab2 employs separate effectors in DCV biogenesis and motility.
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Cites
Highly accurate protein structure prediction with AlphaFold
Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03819-2 · Cited by 43,764 · see citing works
Accurate structure prediction of biomolecular interactions with AlphaFold 3
Abramson, J., Adler, J., Dunger, J., Evans, R., Green, T., Pritzel, A., Ronneberger, O., Willmore, L., Ballard, A. J., Bambrick, J., et al. (2024) · Nature · doi:10.1038/s41586-024-07487-w · Cited by 15,861 · cited 1× · see citing works
“Modelling of the RUFY dimer was performed with AlphaFold 3 (Abramson et al., 2024) (https://alphafoldserver.com/).”
Axonal transport: Driving synaptic function
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Interaction of a mitogen-activated protein kinase signaling module with the neuronal protein JIP3
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“Besides the vesicular motor adaptor role, Syd/JIP3/4 proteins function as important scaffolds and transport adaptors for the JNK MAP kinase (Byrd et al., 2001; Ito et al., 1999; Kelkar et al., 2000).”
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Two Rab2 Interactors Regulate Dense-Core Vesicle Maturation
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- Authors
- Lund, V. K., Chirco, A., Caliari, M., Larsen, A. H., Tang, K. T., Gether, U., Madsen, K. L., Wierer, M., & Kjaerulff, O.
- Affiliations
- University of Copenhagen (DK)
- University of Copenhagen 1 Department of Neuroscience, , Copenhagen N,
- Corresponding author
- Lund, Viktor Karlovich
- ORCID
- Venue
- Journal of Cell Biology
- Publisher
- Rockefeller University Press
- Published
- 2026-01-06
- Volume
- 225
- Issue
- 3
- ISSN
- 0021-9525 (ISSN-L)
- 1540-8140
- PMC
- PMC12772503
- OpenAlex
- W7118924843
- Cited by
- 0
- References
- 6
- FWCI
- 0.00
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- The Journal of Cell Biology (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion, cc-by)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by)
- Funders
- University of Copenhagen
- Novo Nordisk Foundation (NNF19SA0059305, 70287)
- Aage og Johanne Louis-Hansens Fond
- Lundbeck Foundation (RF347-2020-2339, R359-2020-2301)
- ERASMUS program
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
- Keywords
- dense core vesicles, dynein, Rab2, kinesin-1, retrograde transport, axonal transport, neuropeptide release, motor neurons, vesicle motility, vesicle sorting, Drosophila
- MeSH terms
- Animals, Axons, Drosophila melanogaster, Dyneins, Motor Neurons, Kinesins, rab2 GTP-Binding Protein, Secretory Vesicles, Drosophila Proteins
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