Disease relevance of RAB9A

• Rab9 mediates late endosome to trans-Golgi transport and has recently been found to be a key cellular component for human immunodeficiency virus-1, Ebola, Marburg, and measles virus replication, suggesting that it may be a novel target in the development of broad spectrum antiviral drugs [1].
• In addition, preliminary studies using antisense expression indicate that down-regulation of either Rab7 or Rab9 proteins induces severe cell vacuolation that resembles the phenotype seen in fibroblasts from patients with Chediak-Higashi syndrome [2].
• In addition, silencing studies revealed that HIV replication was dependent on the expression of Rab11A, which mediates trans-Golgi-to-plasma-membrane transport, and that increased HIV Gag was sequestered in a CD63+ endocytic compartment in a cell line stably expressing Rab9 siRNA [3].
• Although Rab9 has not been implicated in human immunodeficiency virus (HIV) replication, previous reports suggested that the late endosome is an initiation site for HIV assembly and that TIP47-dependent trafficking out of the late endosome to the trans-Golgi network facilitates the sorting of HIV Env into virions budding at the plasma membrane [3].
• Recombinant human Rab9 fused with the herpes simplex virus VP22 protein fragment was overexpressed, purified, and added to culture medium to induce protein transduction [4].

High impact information on RAB9A

• A functional Rab9 binding site was required for TIP47 stimulation of MPR transport in vivo [5].
• Our results demonstrate a role for Rab7 and Rab9 in the Golgi targeting of glycosphingolipids and suggest a new therapeutic approach for restoring normal lipid trafficking in NP-C cells [6].
• These data provide the first indication that Rab9-mediated endosome to trans-Golgi transport can use a vesicle (rather than a tubular) intermediate [7].
• Cation-independent mannose 6-phosphate receptors are enriched in the Rab9 domain relative to the Rab7 domain [7].
• Rab9-positive transport vesicles fuse with the trans-Golgi network as followed by video microscopy of live cells [7].

Biological context of RAB9A

• The Rab9 structure at near atomic resolution provides an excellent model for structure-based antiviral drug design [1].
• Structure-based sequence alignment of Rab9 with other Rab proteins reveals that its active site consists of residues highly conserved in the Rab GTPase family, implying a common catalytic mechanism [1].
• This effect is Rab9-specific since expression of Rab9 in untransformed NPC1 cells also leads to a reversal of their disease phenotype [8].
• Here we report that ectopic expression of human telomerase reverse transcriptase (hTeRT) in human cells leads to an upregulation of the small GTPase Rab9 and its effector p40 [8].
• During isolation and characterization of these cDNAs a Rab9 pseudogene was identified [2].

Anatomical context of RAB9A

• Rab9 GTPase is required for the transport of mannose 6-phosphate receptors from endosomes to the trans-Golgi network in living cells, and in an in vitro system that reconstitutes this process [9].
• These data are consistent with a model in which p40 and Rab9 act together to drive the process of transport vesicle docking [9].
• Rab9 GTPase regulates late endosome size and requires effector interaction for its stability [10].
• Moreover, Rab9 and the proteins with which it interacts seem critical for the maintenance of specific late endocytic compartments and endosome/lysosome localization [10].
• To explore the importance of Rab9 for microdomain establishment, we depleted the protein from cultured cells [10].

Associations of RAB9A with chemical compounds

• Telomerase immortalization upregulates Rab9 expression and restores LDL cholesterol egress from Niemann-Pick C1 late endosomes [8].
• Here we show that TIP47 also bound directly to the Rab9 guanosine triphosphatase (GTPase) in its active, GTP-bound conformation [5].
• Quantitative analysis of the interactions between prenyl Rab9, GDP dissociation inhibitor-alpha, and guanine nucleotides [11].
• Complex formation could be reconstituted in vitro using recombinant rab9 protein, cytosol, ATP, and geranylgeranyl diphosphate, and was shown to require an intact rab9 carboxy terminus, as well as rab9 geranylgeranylation [12].
• We find that mAtg9 is located in the trans-Golgi network and late endosomes and colocalizes with TGN46, the cation-independent mannose-6-phosphate receptor, Rab7 and Rab9 [13].

Other interactions of RAB9A

• Two sequences corresponded to novel isoforms of Rab2 and Rab9 [14].
• Finally, p40 shows synergy with Rab9 in terms of its ability to stimulate mannose 6-phosphate receptor transport [9].
• Surprisingly, Rab9 stability on late endosomes required interaction with TIP47 [10].
• Rab7 and the Rab9 pseudogene were mapped to chromosomes 3 and 5, respectively, by amplification of their sequences from human monochromosomal somatic cell hybrids [2].
• Active PIKfyve associates with and promotes the membrane attachment of the late endosome-to-trans-Golgi network transport factor Rab9 effector p40 [15].

Analytical, diagnostic and therapeutic context of RAB9A

• The most impaired mutant was indistinguishable from wild-type TIP47 in its circular dichroism spectrum, and mutant proteins that showed decreased Rab9 binding retained full capacity to bind to MPR cytoplasmic domains [16].
• Moreover, co-immunoprecipitation experiments showed that Hook1 physically interacts with endocytic Rab7, Rab9 and Rab11, hence delineating a manifold role for mammalian Hook1 in membrane trafficking events [17].
• Double-label immunofluorescence microscopy and subcellular fractionation studies indicated that NPC1 associates predominantly with late endosomes (Rab9 GTPase-positive vesicles) and, to a lesser extent, with lysosomes and the trans-Golgi network [18].

References