Alternative titles; symbols
HGNC Approved Gene Symbol: RAB8A
Cytogenetic location: 19p13.11 Genomic coordinates (GRCh38): 19:16,111,889-16,134,234 (from NCBI)
Members of the RAS superfamily, such as RAB8A, are small GTP/GDP-binding proteins with an average size of 200 amino acids. The RAS-related proteins of the RAB/YPT family may play a role in the transport of proteins from the endoplasmic reticulum to the Golgi and the plasma membrane (Nimmo et al., 1991).
Using DNA transfection into NIH 3T3 cells, Padua et al. (1984) demonstrated that the human malignant melanoma cell line NK14 contains a novel transforming gene. Nimmo et al. (1991) isolated human MEL genomic clones and cDNAs, as well as a cDNA encoding the mouse MEL homolog. The predicted 206-amino acid human MEL protein shares 97%, 96%, and 51% identity with the dog RAB8, mouse MEL, and mouse YPT1 (RAB1; 179508) proteins, respectively. MEL contains the 4 GTP/GDP-binding sites that are present in all the RAS proteins. The putative effector-binding site of MEL is similar to that of the RAB/YPT proteins. However, MEL contains a C-terminal CAAX motif that is characteristic of many RAS superfamily members but which is not found in YPT1 and the majority of RAB proteins.
Sato et al. (2007) showed that Rab8 is responsible for the localization of apical proteins in intestinal epithelial cells. The authors found that apical peptidases and transporters localized to lysosomes in the small intestine of Rab8-deficient mice. Their mislocalization and degradation in lysosomes led to a marked reduction in the absorption rate of nutrients in the small intestine, and ultimately to death. Ultrastructurally, a shortening of apical microvilli, an increased number of enlarged lysosomes, and microvillus inclusions in the enterocytes were also observed. One patient with microvillus inclusion disease (251850) who showed an identical phenotype to that of Rab8-deficient mice expressed a reduced amount of Rab8. Sato et al. (2007) concluded that RAB8 is necessary for the proper localization of apical proteins and the absorption and digestion of various nutrients in the small intestine.
Omori et al. (2008) identified elipsa, the zebrafish ortholog of TRAF3IP1 (607380), as a component of intraflagellar transport particles, which are involved in the formation and function of cilia. Elipsa interacted with rabaptin-5 (RABEP1; 603616), a regulator of endocytosis, and rabaptin-5 in turn interacted with Rab8. Omori et al. (2008) concluded that elipsa, rabaptin-5, and Rab8 provide a bridge between the intraflagellar transport particle and protein complexes that assemble at the ciliary membrane.
RAB8A regulates cilia assembly by targeting and promoting fusion of vesicles near the ciliary membrane. Tsang et al. (2008) found that RAB8A localized to the centrosome in growing human RPE1 retinal pigment epithelial cells and to the ciliary membrane in quiescent cells. RAB8A bound a central domain of CEP290 (610142) and interacted with CEP290 in both growing and quiescent cells. Both RAB8A and CEP290 interacted with CP110 (609544) in growing cells. Knockdown of CEP290 prevented ciliogenesis in differentiating RPE1 cells and reduced the number of RAB8A foci. Tsang et al. (2008) concluded that RAB8A requires CEP290 for centrosome localization and that CEP290 regulates entry of RAB8A into the cilium during assembly of this organelle.
Hsiao et al. (2009) showed that AHI1 (608894), which is mutated in Joubert syndrome type 3 (JBTS3; 608629), regulated formation of the primary nonmotile cilium via its interaction with RAB8A. Mouse Ahi1 protein localized to a single centriole, the mother centriole, which becomes the basal body of the primary cilium. In mice, RNAi knockdown of Ahi1 expression led to impairments in ciliogenesis. In Ahi1-knockdown cells, Rab8a was destabilized and did not properly localize to the basal body. Defects in the trafficking of endocytic vesicles from the plasma membrane to the Golgi and back to the plasma membrane were observed in Ahi1-knockdown cells. Hsiao et al. (2009) concluded that the distribution and functioning of RAB8A is regulated by AHI1, not only affecting cilium formation, but also vesicle transport.
By coimmunoprecipitation of bovine retinal extract, Murga-Zamalloa et al. (2010) found that Rpgr (312610) interacted with Rab8a. Human RPGR interacted predominantly with the GDP-bound form of human RAB8A and stimulated GDP/GTP exchange. Disease-causing mutations in RPGR diminished its interaction with RAB8A and/or reduced its GDP/GTP exchange activity. Depletion of RPGR in human retinal pigment epithelial cells disrupted association of RAB8A with cilia and resulted in shortened primary cilia.
Using yeast 2-hybrid, pull-down, and coimmunoprecipitation analyses, Nakajo et al. (2016) identified mouse Ehbp1l1 (619583) as a Rab8-binding protein. Ehbp1l1 also bound Bin1 (601248), with the proline-rich domain of Ehbp1l1 interacting with the C-terminal SH3-containing region of Bin1. By interacting, Rab8, Ehbp1l1, and Bin1 stabilized their localization at the ECR. The Rab8-Ehbp1l1-Bin1 complex played a role in transport of apical and basolateral cargo proteins through the ERC to the apical plasma membrane in polarized epithelial cells by sensing and generating membrane tubules to transport cargo, likely with the involvement of dynamin.
Chi et al. (2010) described the phenotypic characteristics of transgenic mice overexpressing wildtype or mutated optineurin (OPTN; 602432). Mutations E50K (602432.0001), H486R, and Optn with a deletion of the first or second leucine zipper were used for overexpression. After 16 months, histologic abnormalities were exclusively observed in the retina of E50K mutant mice, with loss of retinal ganglion cells and connecting synapses in the peripheral retina, thinning of the nerve fiber layer at the optic nerve head at normal intraocular pressure, and massive apoptosis and degeneration of the entire retina. Introduction of the E50K mutation disrupted the interaction between Optn and Rab8. Wildtype Optn and an active GTP-bound form of Rab8 colocalized to the Golgi. The authors concluded that alteration of the Optn sequence can initiate significant retinal degeneration in mice.
Although MEL was isolated as a transforming gene from a melanoma cell line, no linkage between MEL and malignant melanoma (155600) was demonstrable (Nimmo et al., 1989).
As a result of studies of human-mouse and human-hamster somatic cell hybrids, Spurr et al. (1986) demonstrated that the MEL oncogene is located in the segment 19p13.2-q13.2. By linkage analysis using an NcoI RFLP, Nimmo et al. (1989, 1989) mapped the MEL gene to the region of LDLR (606945), i.e., 19p13.2-cen. Bahler et al. (1997) performed cosmid contig mapping indicating that the MEL locus was 800 kb distal to MYO9B (602129) on chromosome 19p13.1.
Bahler, M., Kehrer, I., Gordon, L., Stoffler, H.-E., Olsen, A. S. Physical mapping of human myosin-IXB (MYO9B), the human orthologue of the rat myosin myr 5, to chromosome 19p13.1. Genomics 43: 107-109, 1997. [PubMed: 9226381] [Full Text: https://doi.org/10.1006/geno.1997.4776]
Chi, Z.-L., Akahori, M., Obazawa, M., Minami, M., Noda, T., Nakaya, N., Tomarev, S., Kawase, K., Yamamoto, T., Noda, S., Sasaoka, M., Shimazaki, A., Takada, Y., Iwata, T. Overexpression of optineurin E50K disrupts Rab8 interaction and leads to a progressive retinal degeneration in mice. Hum. Molec. Genet. 19: 2606-2615, 2010. [PubMed: 20388642] [Full Text: https://doi.org/10.1093/hmg/ddq146]
Hsiao, Y.-C., Tong, Z. J., Westfall, J. E., Ault, J. G., Page-McCaw, P. S., Ferland, R. J. Ahi1, whose human ortholog is mutated in Joubert syndrome, is required for Rab8a localization, ciliogenesis and vesicle trafficking. Hum. Molec. Genet. 18: 3926-3941, 2009. [PubMed: 19625297] [Full Text: https://doi.org/10.1093/hmg/ddp335]
Murga-Zamalloa, C. A., Atkins, S. J., Peranen, J., Swaroop, A., Khanna, H. Interaction of retinitis pigmentosa GTPase regulator (RPGR) with RAB8A GTPase: implications for cilia dysfunction and photoreceptor degeneration. Hum. Molec. Genet. 19: 3591-3598, 2010. [PubMed: 20631154] [Full Text: https://doi.org/10.1093/hmg/ddq275]
Nakajo, A., Yoshimura, S., Togawa, H., Kunii, M., Iwano, T., Izumi, A., Noguchi, Y. Watanabe, A., Goto, A., Sato, T., Harada, A. EHBP1L1 coordinates Rab8 and Bin1 to regulate apical-directed transport in polarized epithelial cells. J. Cell Biol. 212: 297-306, 2016. [PubMed: 26833786] [Full Text: https://doi.org/10.1083/jcb.201508086]
Nimmo, E., Padua, R.-A., Hughes, D., Brook, J. D., Williamson, R., Johnson, K. J. Confirmation and refinement of the localisation of the c-MEL locus on chromosome 19 by physical and genetic mapping. Hum. Genet. 81: 382-384, 1989. [PubMed: 2564840] [Full Text: https://doi.org/10.1007/BF00283697]
Nimmo, E. R., Sanders, P. G., Padua, R. A., Hughes, D., Williamson, R., Johnson, K. J. The MEL gene: a new member of the RAB/YPT class of RAS-related genes. Oncogene 6: 1347-1351, 1991. [PubMed: 1886711]
Nimmo, E., Williamson, R., Johnson, K. Localization of the c-MEL gene to 19(cen-p13.2). (Abstract) Cytogenet. Cell Genet. 51: 1053 only, 1989.
Omori, Y., Zhao, C., Saras, A., Mukhopadhyay, S., Kim, W., Furukawa, T., Sengupta, P., Veraksa, A., Malicki, J. elipsa is an early determinant of ciliogenesis that links the IFT particle to membrane-associated small GTPase Rab8. Nature Cell Biol. 10: 437-444, 2008. [PubMed: 18364699] [Full Text: https://doi.org/10.1038/ncb1706]
Padua, R. A., Barrass, N., Currie, G. A. A novel transforming gene in a human malignant melanoma cell line. Nature 311: 671-673, 1984. [PubMed: 6090953] [Full Text: https://doi.org/10.1038/311671a0]
Sato, T., Mushiake, S., Kato, Y., Sato, K., Sato, M., Takeda, N., Ozono, K., Miki, K., Kubo, Y., Tsuji, A., Harada, R., Harada, A. The Rab8 GTPase regulates apical protein localization in intestinal cells. Nature 448: 366-369, 2007. [PubMed: 17597763] [Full Text: https://doi.org/10.1038/nature05929]
Spurr, N. K., Hughes, D., Goodfellow, P. N., Brook, J. D., Padua, R. A. Chromosomal assignment of c-MEL, a human transforming oncogene, to chromosome 19(p13.2-q13.2). Somat. Cell Molec. Genet. 12: 637-640, 1986. [PubMed: 3466361] [Full Text: https://doi.org/10.1007/BF01671949]
Tsang, W. Y., Bossard, C., Khanna, H., Peranen, J., Swaroop, A., Malhotra, V., Dynlacht, B. D. CP110 suppresses primary cilia formation through its interaction with CEP290, a protein deficiency in human ciliary disease. Dev. Cell 15: 187-197, 2008. [PubMed: 18694559] [Full Text: https://doi.org/10.1016/j.devcel.2008.07.004]