Spatial regulation of ARL3 and GSF‐mediated lipidated cargo trafficking in the primary cilium

Lipid‐modified proteins are essential for ciliary signaling and structure, but their hydrophobic modifications hinder cytosolic transport and selective delivery. GDI ‐like solubilizing factors ( GSFs ), such as PDE6D and UNC119A /B, bind lipid moieties to shield cargo proteins and enable diffusion. However, the mechanisms that govern spatially restricted cargo release—particularly at the primary cilium—are not fully elucidated yet. In this Review, we highlight the central role of the small G protein ARL3 and its regulators in mediating selective release of lipidated cargoes. We discuss ARL13B , a ciliary‐localized guanine nucleotide exchange factor ( GEF ) for ARL3 , and BART , a co‐ GEF that enhances ARL3 activation by relieving autoinhibition. In contrast, RP2 , a GTPase ‐activating protein ( GAP ) at the ciliary base, likely inactivates ARL3 outside the cilium, establishing a spatial ARL3 · GTP gradient that restricts cargo release. Additional specificity arises from ARL2 exclusion from the cilium, differential GSF –cargo binding affinities, and putative docking platforms such as RPGR . Disruption of this pathway is implicated in ciliopathies, including Joubert syndrome. Current models and recent findings provide a framework for understanding spatial GTPase signaling in ciliary transport.