Journal
CURRENT BIOLOGY
Volume 27, Issue 17, Pages 2569-+Publisher
CELL PRESS
DOI: 10.1016/j.cub.2017.07.013
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Funding
- National Basic Research Program of China [2013CB910103]
- Howard Hughes Medical Institute
- NIH [R01 NS048392, R01 GM089933, P40 OD010440]
- JSPS KAKENHI [16H06536, 17H05010]
- Tomizawa Jun-ichi and Keiko Fund of Molecular Biology
- Daiichi Sankyo Foundation of Life Science
- Naito Foundation
- Brain Science Foundation
- Stanford Graduate Fellowship
- National Natural Science Foundation of China [31428009]
- Grants-in-Aid for Scientific Research [17H05010] Funding Source: KAKEN
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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.
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