An Arf-like Small G Protein, ARL-8, Promotes the Axonal Transport of Presynaptic Cargoes by Suppressing Vesicle Aggregation

Abstract

SUMMARY Presynaptic assembly requires the packaging of requisite proteins into vesicular cargoes in the cell soma, their long-distance microtubule-dependent transport down the axon and finally, their reconstitution into functional complexes at prespecified sites. Despite the identification of several molecules that contribute to these events, the regulatory mechanisms defining such discrete states remain elusive. We report the characterization of an Arf-like small G protein, ARL-8, required during this process. arl-8 mutants prematurely accumulate presynaptic cargoes within the proximal axon of several neuronal classes, with a corresponding failure to assemble presynapses distally. This proximal accumulation requires the activity of several molecules known to catalyze presynaptic assembly. Dynamic imaging studies reveal that arl-8 mutant vesicles exhibit an increased tendency to form immotile aggregates during transport. Together, these results suggest that arl-8 promotes a trafficking identity for presynaptic cargoes, facilitating their efficient transport by repressing premature self-association.

Regulation of synaptic stability by AMPA receptor reverse signaling

“…S3A). A similar relationship between the size of presynaptic puncta and stability also was reported recently in Caenorhabditis elegans (28). Further, larger Syn-GFP puncta were much more likely to colocalize with bassoon, a component of the active zone (SI Appendix, Fig.…”

Arf-like GTPase Arl8: Moving from the periphery to the center of lysosomal biology

“…For instance, in C. elegans, Arl8 regulates the transport and spatial distribution of presynaptic proteins by direct binding to the kinesin motor UNC-04/KIF1A in neuronal cells. 21,44 Together, these studies highlight the fact that Arl8b functions in different cell types to regulate the kinesin-dependent movement of lysosomes.…”

“…41 Acting along with kinesin KIF1A, Arl8b also regulates the transport of synaptic vesicles in C. elegans. 21,44 As several diseases arise from defects in the biogenesis and function LROs, it will be important in the future to explore the potential role of Arl8 in transport of LROs and their exocytosis. Additionally, identification of factors that regulate GDP-GTP cycle of Arl8 will reveal mechanistic insights into how this small GTPase is recruited to lysosomal membranes.…”

“…20 Arl8 is emerging as an important regulator of lysosome motility and membrane trafficking in several organisms. [20][21][22][23][24][25] In this review, we provide the first comprehensive overview of the known functions of the Arl8 family, particularly Arl8b, and highlight the interaction of Arl8b with effector proteins and its function in regulating the biology of the lysosome.…”

ARF-like Protein 16 (ARL16) Inhibits RIG-I by Binding with Its C-terminal Domain in a GTP-dependent Manner

“…ARFrelated protein ARLs, including ARL1 and ARL2, are also involved in membrane trafficking or organizing the cytoskeleton (38,(62)(63)(64). ARL4 may function in the nucleus (65); ARL8 promotes axonal transport (28); while ARL13 and ARL3 coordinate intraflagellar transport and ciliogenesis (40). However, most ARL proteins are so far relatively poorly characterized.…”