ELKS1 Captures Rab6-Marked Vesicular Cargo in Presynaptic Nerve Terminals

Neurons face unique transport challenges. They need to deliver cargo over long axonal distances and to many presynaptic nerve terminals. Rab GTPases are master regulators of vesicular traffic, but essential presynaptic Rabs have not been identified. Here, we find that Rab6, a Golgi-derived GTPase for constitutive secretion, associates with mobile axonal cargo and localizes to nerve terminals. ELKS1 is a stationary presynaptic protein with Golgin homology that binds to Rab6. Knockout and rescue experiments for ELKS1 and Rab6 establish that ELKS1 captures Rab6 cargo. The ELKS1-Rab6-capturing mechanism can be transferred to mitochondria by mistargeting ELKS1 or Rab6 to them. We conclude that nerve terminals have repurposed mechanisms from constitutive exocytosis for their highly regulated secretion. By employing Golgin-like mechanisms with anchored ELKS extending its coiled-coils to capture Rab6 cargo, they have spatially separated cargo capture from fusion. ELKS complexes connect to active zones and may mediate vesicle progression toward release sites. [Display omitted] •Active Rab6 labels mobile presynaptic cargo in axons of central neurons•ELKS1 is a Golgin-like protein that captures Rab6 cargo in nerve terminals•ELKS1 is spread throughout the boutons, and its Rab6 binding is required for capture•Neurons have re-purposed a cargo-capturing mechanism from constitutive secretion Nyitrai et al. show that the small GTPase Rab6 is associated with mobile axonal cargo. ELKS1 is a broadly distributed presynaptic protein that captures cargo via binding to Rab6. Hence, nerve terminals have adapted a Golgin-like mechanism for vesicle capture and have spatially separated capture from exocytotic sites for regulation.