ARL8 dependent autoinhibition of SKIP regulates its association with kinesin-1

Intracellular transport and positioning of organelles rely on coupling to motor proteins that move bidirectionally along microtubule tracks. Coupling of organelles to motors is mediated by specific adaptor proteins. The correct spatio-temporal functions of the motors are crucial to maintain cellular processes. Indeed, malfunctions in this machinery are the cause of numerous pathologies including amyotrophic-lateral-sclerosis and hereditary-spastic-paraplegia. Here, we focused on lysosomes, which are highly dynamic organelles. Recent evidence indicates that the precise positioning of lysosomes in the cell is important for autophagy, nutrient signaling and plasma membrane repair. The outward movement of lysosomes is regulated by a lysosome-associated complex named BORC that initiates a chain of interactions involving the small GTPase ARL8, the adaptor protein SKIP, and kinesin-1. We used bioinformatics, biochemical and cell biology tools to identify elements that regulate lysosome positioning, focusing on the adaptor protein SKIP. We found that dimerization of SKIP is required for its function. Most importantly, we discovered that SKIP is inhibited by an intra-molecular interaction between its N- and C-terminal parts. This inhibition is relieved by interaction with ARL8, indicating that ARL8 promotes conformational activation of SKIP for coupling of lysosomes to kinesin-1. More generally, these findings uncover a novel regulatory mechanism in which an organelle adaptor changes from an autoinhibited to an active conformation upon interaction with regulators on the organellar membrane.