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.