GDImediated

GDI-mediated refers to the regulatory actions of GDP-dissociation inhibitors (GDIs) on the Rab family of small GTPases, which are central drivers of intracellular vesicle trafficking. GDIs control the localization and activity of Rab proteins by cycling them between membrane-bound and cytosolic pools, thus shaping the flow of vesicles through the cell’s endomembrane system.

In their mechanism, GDIs bind Rab proteins in the GDP-bound state and extract them from membranes by masking the hydrophobic prenylated tails. Once in the cytosol, Rab-GDI complexes keep Rab in an inactive conformation, shielding them from spontaneous nucleotide exchange. Release of Rab from GDI is driven by factors such as GDI displacement factors (GDFs) or Rab effectors, after which Rab can associate with specific membranes. There, guanine nucleotide exchange factors (GEFs) promote exchange of GDP for GTP, reactivating Rab and guiding vesicle budding, transport, docking, and fusion.

This regulatory axis is essential for maintaining the fidelity and timing of vesicular trafficking across organelles including the Golgi, endosomes, lysosomes, and the plasma membrane. GDIs also participate in Rab recycling by enabling the retrieval of Rab proteins after vesicle fusion events, ensuring a ready supply of Rab for subsequent rounds of trafficking.

Humans express multiple GDI proteins, notably GDI1 and GDI2, with GDI1 enriched in neurons. Dysregulation of GDI-Rab cycling has been linked to trafficking defects implicated in neurodevelopmental and neurodegenerative diseases, as well as certain cancers, underscoring the importance of GDI-mediated control in cellular homeostasis. Structural and biochemical studies continue to elucidate the specificity and regulation of GDI-Rab interactions.