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bioRxiv · 10.1101/2025.05.28.656585

Rab2 and Arl8/BORC control retrograde axonal transport of dense core vesicles via Syd/dJIP3/4 and RUFY dynein adaptors

Lund, V. K.·Chirco, A.·Caliari, M.·Larsen, A. H.·Gether, U.·Madsen, K. L.·Wierer, M.·Kjaerulff, O.
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Abstract

Neuropeptide-containing dense core vesicles (DCVs) are generated in the neuronal cell body and circulate throughout the axonal arbor to supply distal release sites. This circulation depends on the anterograde kinesin-1 and kinesin-3 motors and the retrograde dynein-dynactin motor. While kinesin-3 is recruited to DCVs with the aid of the small GTPase Arl8, it is unclear how dynein and kinesin-1 are recruited and regulated. Here we show that DCV motility in Drosophila (fruit flies) depends on the dynein and kinesin-1 adaptor Sunday Driver/dJIP3/4 (Syd) and the novel dynein adaptor RUFY. Syd and RUFY bind each other; moreover, Syd binds the DCV-located GTPase Rab2 that controls retrograde DCV transport, and RUFY binds Arl8. Disruption of Rab2, Syd, RUFY, dynein, and the Arl8 activator BORC all produce a similar DCV axonal transport phenotype characterized by axonal accumulation of immobile DCVs and a selective reduction in retrograde DCV flux. Our data suggest a model where dynein is recruited and activated by a complex of Syd and RUFY, which is anchored to DCVs by a Rab2- and Arl8-dependent mechanism. Lastly, we show that loss of Rab2 results in missorting of the DCV membrane proteins VMAT and Synaptotagmin-, similar to the reported effect of Rab2 deletion on the sorting of synaptic vesicle and active zone proteins. However, disruption of Syd, RUFY or dynein does not phenocopy the Rab2-specific VMAT sorting defect, suggesting that Rab2 employs separate effectors in DCV biogenesis and motility.

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Lund, V. K., Chirco, A., Caliari, M., Larsen, A. H., Gether, U., Madsen, K. L., Wierer, M., Kjaerulff, O.. 2025-06-01. Rab2 and Arl8/BORC control retrograde axonal transport of dense core vesicles via Syd/dJIP3/4 and RUFY dynein adaptors. https://doi.org/10.1101/2025.05.28.656585

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