Rabs in the driving seat: Coordinating vesicular traffic and membrane contact site dynamics

Rab GTPases are central regulators of intracellular membrane organization, ensuring the specificity and directionality of vesicular transport. Operating as 'molecular switches,' Rab GTPases cycle between an active GTP-bound and an inactive GDP-bound state, a process regulated by GEFs (guanine nucleotide exchange factors) and GAPs (GTPase-activating proteins). The dynamic switch-like behaviour and compartment-specific localization of Rab GTPases establish membrane identity and generate discrete membrane subdomains, providing spatiotemporal control over intracellular trafficking events. Rab GTPases also facilitate compartment maturation through coordinated Rab conversion, leading to transitions between different membrane identities. Membrane-localized Rab GTPases function as a recruitment platform for a cohort of effector proteins, which regulate the sequential steps of vesicular transport. The features discussed above also enable Rabs to participate in the formation of membrane contact sites, which facilitate direct transport of phospholipids and small molecules between compartments and regulate organelle motility and positioning. Here we review current insights into the mechanisms governing Rab GTPase regulation, including post translational modifications and interactions with effectors. We also discuss their roles in membrane domain formation, compartment maturation via Rab cascades, and non-vesicular communication pathways. These findings enhance our understanding of the multifaceted functions of Rab GTPases in compartmentalization and highlight emerging areas for future investigation.