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Curr Biol. 2017 Sep 11;27(17):2569-2578.e4. doi: 10.1016/j.cub.2017.07.013. Epub 2017 Aug 17.

BORC Regulates the Axonal Transport of Synaptic Vesicle Precursors by Activating ARL-8.

Author information

1
Frontier Research Institute for Interdisciplinary Sciences and Graduate School of Life Sciences, Tohoku University, Aramaki Aza Aoba 6-3, Aoba-ku, Sendai, Miyagi 980-8578, Japan. Electronic address: shinsuke.niwa.c8@tohoku.ac.jp.
2
Howard Hughes Medical Institute, Department of Biology, Stanford University, 385 Serra Mall, Stanford, CA 94305, USA.
3
Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 279 Campus Drive, Stanford, CA 94305, USA.
4
National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Chaoyang District, Beijing 100101, China.
5
Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 279 Campus Drive, Stanford, CA 94305, USA. Electronic address: nachury@stanford.edu.
6
Howard Hughes Medical Institute, Department of Biology, Stanford University, 385 Serra Mall, Stanford, CA 94305, USA; National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Chaoyang District, Beijing 100101, China. Electronic address: kangshen@stanford.edu.

Abstract

Axonal transport of synaptic vesicle precursors (SVPs) is essential for synapse development and function. The conserved ARF-like small GTPase ARL-8 is localized to SVPs and directly activates UNC-104/KIF1A, the axonal-transport kinesin for SVPs in C. elegans. It is not clear how ARL-8 is activated in this process. Here we show that part of the BLOC-1-related complex (BORC), previously shown to regulate lysosomal transport, is required to recruit and activate ARL-8 on SVPs. We found mutations in six BORC subunits-blos-1/BLOS1, blos-2/BLOS2, snpn-1/Snapin, sam-4/Myrlysin, blos-7/Lyspersin, and blos-9/MEF2BNB-cause defects in axonal transport of SVPs, leading to ectopic accumulation of synaptic vesicles in the proximal axon. This phenotype is suppressed by constitutively active arl-8 or unc-104 mutants. Furthermore, SAM-4/Myrlysin, a subunit of BORC, promotes the GDP-to-GTP exchange of ARL-8 in vitro and recruits ARL-8 onto SVPs in vivo. Thus, BORC regulates the axonal transport of synaptic materials and synapse formation by controlling the nucleotide state of ARL-8. Interestingly, the other two subunits of BORC essential for lysosomal transport, kxd-1/KXD1 and blos-8/Diaskedin, are not required for the SVP transport, suggesting distinct subunit requirements for lysosomal and SVP trafficking.

KEYWORDS:

ARL-8; BORC; KIF1A; UNC-104; axonal transport; synapse; synaptic vesicles

PMID:
28823680
PMCID:
PMC5693321
DOI:
10.1016/j.cub.2017.07.013
[Indexed for MEDLINE]
Free PMC Article

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