Rab9

Rab9 is a member of the Rab family of small GTPases that regulate intracellular membrane traffic. In mammals, Rab9 proteins, primarily Rab9A, control retrograde transport from late endosomes to the trans-Golgi network (TGN), a pathway important for recycling receptors and lysosomal enzyme sorting.

Rab9 functions as a molecular switch, cycling between an active GTP-bound state and an inactive GDP-bound state. When in the GTP-bound form, Rab9 associates with late endosomal membranes and recruits effector proteins to promote vesicle budding, cargo selection, and tethering or fusion with target compartments. One well-characterized Rab9 effector is TIP47, which participates in the sorting and transport of cargo such as the mannose-6-phosphate receptor (CI-MPR). The activity of Rab9 is regulated by guanine nucleotide exchange factors (GEFs) that activate it and GTPase-activating proteins (GAPs) that inactivate it, enabling precise control of trafficking steps.

Localization and distribution: Rab9 localizes predominantly to late endosomes and the TGN, coordinating cargo movement between these compartments. It is a conserved component of the Rab GTPase system, with Rab9A being the dominant form in many tissues. A paralog, Rab9B, is present in some vertebrates, though its specific role is less clearly defined.

Structure: Rab9 proteins are about 200 amino acids long and share the conserved motifs of the Ras superfamily, including regions responsible for nucleotide binding and hydrolysis.

Clinical relevance: Disruption of Rab9-dependent retrograde transport can affect lysosomal enzyme sorting and overall cellular homeostasis. Specific human diseases directly attributed to Rab9 mutations are not well established, but proper Rab9 function is important for endosome-to-TGN trafficking and lysosome biogenesis.