Alternative titles; symbols
HGNC Approved Gene Symbol: RANBP2
Cytogenetic location: 2q13 Genomic coordinates (GRCh38): 2:108,719,482-109,842,301 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q13 | {Encephalopathy, acute, infection-induced, 3, susceptibility to} | 608033 | Autosomal dominant | 3 |
The RANBP2 is a component of the nuclear pore complex and plays a role in facilitation of protein import and export, sumoylation of protein cargoes, intracellular trafficking, and energy maintenance (Neilson et al., 2009).
By 2-hybrid screen with RAN (601179) as bait, Yokoyama et al. (1995) cloned RANBP2, which encodes a very large protein of 3,224 amino acids that was immunolocalized to the nuclear pore complex. The protein has an N-terminal 700-residue leucine-rich domain (LRD), 4 motifs in common with RANBP1 (601180), 8 zinc finger motifs, and a C terminus related to cyclophilin (123840). The authors showed that an antibody directed against RANBP2 inhibited nuclear import. RAN is a small GTP-binding protein of the RAS superfamily (see 190020) that is associated with the nuclear membrane and is thought to control a variety of cellular functions through its interactions with other proteins (Yokoyama et al., 1995). Beddow et al. (1995) described a nearly identical partial cDNA which contains a motif of about 150 residues that stabilizes the GTP-bound state of RAN. A mutation in that domain markedly reduced RAN binding. The gene is also referred to as NUP358 (Wu et al., 1995).
Pichler et al. (2002) showed that the nucleoporin RANBP2 has SUMO1 (601912) E3-like activity. RANBP2 directly interacts with the E2 enzyme UBC9 (601661) and strongly enhances SUMO1 transfer from UBC9 to the SUMO1 target SP100 (604585). The E3-like activity is contained within a 33-kD domain of RANBP2 that lacks RING finger motifs and does not resemble PIAS (see 603566) family proteins. These findings placed sumoylation at the cytoplasmic filaments of the nuclear pore complexes and suggested that, at least for some substrates, modification and nuclear import are linked events.
Castagnet et al. (2003) provided evidence of RPGRIP1 (605446) association in vivo with RANBP2 at the nuclear rim of a restricted population of amacrine neurons and in the transformed mouse photoreceptor cell line 661W. Their data implicated a role of RANBP2 in the pathogenesis of neuroretinopathies and as a docking station to mediate the nucleocytoplasmic RPGRIP1 isoforms and their interaction with other partners in amacrine and 661W neurons.
Aslanukov et al. (2006) demonstrated that RANBP2 associated in vitro and in vivo and colocalized with COX11 (603648) and HKI (142600) via the its leucine-rich domain. RANBP2 also exhibited strong chaperone activity toward intermediate and mature folding species of COX11, and RANPB2 suppressed COX11 inhibition of HKI.
Using bovine and murine constructs, Cai et al. (2001) showed that a Ranbp2 domain between Ran GTPase-binding domains 2 and 3 bound to 2 kinesin microtubule-based motor proteins, Kif5b (602809) and Kif5c (604593), in neurons. The kinesin light chain (see KLC1; 600025) and Ran GTPase were part of this Ranbp2 microassembly complex. Cai et al. (2001) concluded that RANBP2 is an integrator of nuclear and cytoplasmic trafficking pathways in neurons.
Um et al. (2006) showed that parkin (PARK2; 602544) bound and ubiquitinated RANBP2, causing its proteasome-dependent degradation. By causing the degradation of RANBP2, parkin also controlled the intracellular levels of sumoylated HDAC4 (605314), a RANBP2 target involved in myogenesis and inhibition of muscle differentiation.
By analyzing the virus capsid uncoating process during adenovirus infection in HeLa cells, Strunze et al. (2011) found that the incoming virus particle moved toward the nucleus via microtubules and docked to the nuclear pore complex (NPC) by interacting with Nup214 (114350). Adenovirus subsequently recruited kinesin-1 using viral capsid protein IX, which interacted with kinesin-1 light chain KLC1/KLC2 (611729). Kinesin-1 then bound to NUP358, which was attached to the NUP214/NUP88 (602552) complex, through its heavy chain KIF5C (604593) and disrupted the viral capsid and dislocated NUP214, NUP358, and NUP62 (605815) from the central NPC to the periphery. Disruption of the NPC increased permeability of the nuclear envelope and facilitated entry of viral DNA into the nucleus.
Rasaiyaah et al. (2013) showed that HIV-1 capsid mutants N74D and P90A, which are impaired for interaction with cofactors (CPSF6; 604979) and cyclophilins (NUP358 and CYPA, 123840), respectively, cannot replicate in primary human monocyte-derived macrophages because they trigger innate sensors leading to nuclear translocation of NFKB (see 164011) and IRF3 (603734), the production of soluble type I IFN, and induction of an antiviral state. Depletion of CPSF6 with short hairpin RNA expression allowed wildtype virus to trigger innate sensors and IFN production. In each case, suppressed replication was rescued by IFN-receptor blockade, demonstrating a role for IFN in restriction. IFN production is dependent on viral reverse transcription but not integration, indicating that a viral reverse transcription product comprises the HIV-1 pathogen-associated molecular pattern. Finally, Rasaiyaah et al. (2013) demonstrated that they could pharmacologically induce wildtype HIV-1 infection to stimulate IFN secretion and an antiviral state using a nonimmunosuppressive cyclosporine analog. The authors concluded that HIV-1 has evolved to use CPSF6 and cyclophilins to cloak its replication, allowing evasion of innate immune sensors and induction of a cell-autonomous innate immune response in primary human macrophages.
Crystal Structure
Reverter and Lima (2005) described the 3.0-angstrom crystal structure of a 4-protein complex of UBC9, a NUP358/RANBP2 E3 ligase domain (IR1-M), and SUMO1 conjugated to the carboxy-terminal domain of RANGAP1 (602362). Structural insights, combined with biochemical and kinetic data obtained with additional substrates, supported a model in which NUP358/RANBP2 acts as an E3 by binding both SUMO and UBC9 to position the SUMO-E2-thioester in an optimal orientation to enhance conjugation.
By fluorescence in situ hybridization, Krebber et al. (1997) mapped the RANBP2 gene to chromosome 2q11-q13. Fauser et al. (2001) mapped the mouse homolog to chromosome 10 by radiation hybrid mapping.
In affected members of 10 unrelated families with acute necrotizing encephalopathy (ANE, IIAE3; 608033), Neilson et al. (2009) identified a heterozygous mutation in the RANBP2 gene (601181.0001). Haplotype analysis did not support a founder effect. Two additional affected families were found to carry different heterozygous mutations in the RANBP2 gene (601181.0002 and 601181.0003). Neilson et al. (2009) concluded that mutations in the RANBP2 gene predispose to ANE, but by themselves are insufficient to make the phenotype fully penetrant; additional genetic and environmental factors are required. Four more affected families did not carry RANBP2 mutations, indicating genetic heterogeneity.
Aslanukov et al. (2006) generated a mouse model with a genetically disrupted Ranbp2 locus and found that Ranbp2 -/- was embryonically lethal. Ranbp2 +/- mice had a pronounced decrease in HKI and ATP levels selectively in the central nervous system, and exhibited deficits in growth rates and glucose catabolism without impairment of glucose uptake and gluconeogenesis. These phenotypes were accompanied by a decrease in the electrophysiologic responses of photosensory and postreceptoral neurons. Aslanukov et al. (2006) concluded that RANBP2 and its partners are critical modulators of neuronal HKI, glucose catabolism, and energy homeostasis.
Dawlaty et al. (2008) created a series of mice with graded expression of Ranbp2 from normal to zero by crossing mice with wildtype, hypomorphic, and knockout alleles. Ranbp2 -/- mice died during embryogenesis, but all Ranbp2-hypomorphic mice were overtly indistinguishable from wildtype. Nucleocytoplasmic transport of polyadenylated mRNA was normal in all hypomorphic mouse embryonic fibroblasts (MEFs). However, karyotype analysis revealed an inverse correlation between Ranbp2 protein level and the percentage of aneuploidy in splenocytes and MEF, and aneuploidy was due to the formation of anaphase-bridges. Topoisomerase II-alpha (TOP2A; 126430), which decatenates sister centromeres prior to anaphase onset to prevent bridges, failed to accumulate at inner centromeres when Ranbp2 levels were low. Ranbp2 sumoylated Top2a in mitosis, and this modification was required for proper localization of Top2a at inner centromeres. Mice with low amounts of Ranbp2 were highly sensitive to tumor formation. Dawlaty et al. (2008) concluded that RANBP2 is a chromosomal instability gene that regulates TOP2A by sumoylation and suppresses tumorigenesis.
In affected members of a family with acute necrotizing encephalopathy (IIAE3; 608033), Neilson et al. (2009) identified a heterozygous 1880C-T transition in the RANBP2 gene, resulting in a thr585-to-met (T585M) substitution in the leucine-rich domain (LRD). The same heterozygous mutation was found in 9 of 15 additional families segregrating with disease. Haplotype analysis did not indicate a founder effect. The mutation was not found in 384 controls, 1,000 individuals from the CEPH genome diversity panel, or in 1,297 multiple sclerosis (126200) patients.
Lonnqvist et al. (2011) identified a heterozygous T585M mutation in 6 affected members of a 3-generation Finnish family with ANE1. Five patients had onset of episodes between age 7 months and 6 years; 1 had a single episode at age 12 years as a sequel of mumps. Two patients had recurrence in childhood. One patient had complete recovery, and 3 patients had recovery with only minor motor impairment, 1 of whom also developed seizures responsive to medication. A fifth patient, who had 2 episodes, was severely mentally retarded with intractable epilepsy at age 35, and a sixth patient had learning disabilities and severe visual impairment. All episodes were preceded by common viral infections. Brain MRI showed that the external capsule and mamillary bodies were affected in all, and the brainstem and thalami in 3.
In affected members of a family with acute necrotizing encephalopathy (608033), Neilson et al. (2009) identified a heterozygous 2085C-T transition in the RANBP2 gene, resulting in a thr653-to-ile (T653I) substitution in a highly conserved residue in the LRD. The mutation was not found in 200 controls.
In affected members of a family with acute necrotizing encephalopathy (608033), Neilson et al. (2009) identified a heterozygous 2094A-G transition in the RANBP2 gene, resulting in an ile656-to-val (I656V) substitution in a highly conserved residue in the LRD. The mutation was not found in 200 controls.
Aslanukov, A., Bhowmick, R., Guruju, M., Oswald, J., Raz, D., Bush, R. A., Sieving, P. A., Lu, X., Bock, C. B., Ferreira, P. A. RanBP2 modulates Cox11 and hexokinase I activities and haploinsufficiency of RanBP2 causes deficits in glucose metabolism. PLoS Genet. 2: e177, 2006. Note: Electronic Article. [PubMed: 17069463] [Full Text: https://doi.org/10.1371/journal.pgen.0020177]
Beddow, A. L., Richards, S. A., Orem, N. R., Macara, I. G. The Ran/TC4 GTPase-binding domain: identification by expression cloning and characterization of a conserved sequence motif. Proc. Nat. Acad. Sci. 92: 3328-3332, 1995. [PubMed: 7724562] [Full Text: https://doi.org/10.1073/pnas.92.8.3328]
Cai, Y., Singh, B. B., Aslanukov, A., Zhao, H., Ferreira, P. A. The docking of kinesins, KIF5B and KIF5C, to Ran-binding protein 2 (RanBP2) is mediated via a novel RanBP2 domain. J. Biol. Chem. 276: 41594-41602, 2001. [PubMed: 11553612] [Full Text: https://doi.org/10.1074/jbc.M104514200]
Castagnet, P., Mavlyutov, T., Cai, Y., Zhong, F., Ferreira, P. RPGRIP1s with distinct neuronal localization and biochemical properties associate selectively with RanBP2 in amacrine neurons. Hum. Molec. Genet. 12: 1847-1863, 2003. [PubMed: 12874105] [Full Text: https://doi.org/10.1093/hmg/ddg202]
Dawlaty, M. M., Malureanu, L., Jeganathan, K. B., Kao, E., Sustmann, C., Tahk, S., Shuai, K., Grosschedl, R., van Deursen, J. M. Resolution of sister centromeres requires RanBP2-mediated SUMOylation of topoisomerase II-alpha. Cell 133: 103-115, 2008. [PubMed: 18394993] [Full Text: https://doi.org/10.1016/j.cell.2008.01.045]
Fauser, S., Aslanukov, A., Roepman, R., Ferreira, P. A. Genomic organization, expression, and localization of murine Ran-binding protein 2 (RanBP2) gene. Mammalian Genome 12: 406-415, 2001. [PubMed: 11353387] [Full Text: https://doi.org/10.1007/s003350010291]
Krebber, H., Bastians, H., Hoheisel, J., Lichter, P., Ponstingl, H., Joos, S. Localization of the gene encoding the Ran-binding protein RanBP2 to human chromosome 2q11-q13 by fluorescence in situ hybridization. Genomics 43: 247-248, 1997. [PubMed: 9244446] [Full Text: https://doi.org/10.1006/geno.1997.4777]
Lonnqvist, T., Isohanni, P., Valanne, L., Olli-Lahdesmaki, T., Suomalainen, A., Pihko, H. Dominant encephalopathy mimicking mitochondrial disease. Neurology 76: 101-103, 2011. [PubMed: 21205700] [Full Text: https://doi.org/10.1212/WNL.0b013e318203e908]
Neilson, D. E., Adams, M. D., Orr, C. M. D., Schelling, D. K., Eiben, R. M., Kerr, D. S., Anderson, J., Bassuk, A. G., Bye, A. M., Childs, A.-M., Clarke, A., Crow, Y. J., and 26 others. Infection-triggered familial or recurrent cases of acute necrotizing encephalopathy caused by mutations in a component of the nuclear pore, RANBP2. Am. J. Hum. Genet. 84: 44-51, 2009. [PubMed: 19118815] [Full Text: https://doi.org/10.1016/j.ajhg.2008.12.009]
Pichler, A., Gast, A., Seeler, J. S., Dejean, A., Melchior, F. The nucleoporin RanBP2 has SUMO1 E3 ligase activity. Cell 108: 109-120, 2002. [PubMed: 11792325] [Full Text: https://doi.org/10.1016/s0092-8674(01)00633-x]
Rasaiyaah, J., Tan, C. P., Fletcher, A. J., Price, A. J., Blondeau, C., Hilditch, L., Jacques, D. A., Selwood, D. L., James, L. C., Noursadeghi, M., Towers, G. J. HIV-1 evades innate immune recognition through specific cofactor recruitment. Nature 503: 402-405, 2013. [PubMed: 24196705] [Full Text: https://doi.org/10.1038/nature12769]
Reverter, D., Lima, C. D. Insights into E3 ligase activity revealed by a SUMO-RanGAP1-Ubc9-Nup358 complex. (Letter) Nature 435: 687-692, 2005. [PubMed: 15931224] [Full Text: https://doi.org/10.1038/nature03588]
Strunze, S., Engelke, M. F., Wang, I-H., Puntener, D., Boucke, K., Schleich, S., Way, M., Schoenenberger, P., Burckhardt, C. J., Greber, U. F. Kinesin-1-mediated capsid disassembly and disruption of the nuclear pore complex promote virus infection. Cell Host Microbe 10: 210-223, 2011. [PubMed: 21925109] [Full Text: https://doi.org/10.1016/j.chom.2011.08.010]
Um, J. W., Min, D. S., Rhim, H., Kim, J., Paik, S. R., Chung, K. C. Parkin ubiquitinates and promotes the degradation of RanBP2. J. Biol. Chem. 281: 3595-3603, 2006. [PubMed: 16332688] [Full Text: https://doi.org/10.1074/jbc.M504994200]
Wu, J., Matunis, M. J., Kraemer, D., Blobel, G., Coutavas, E. Nup358, a cytoplasmically exposed nucleoporin with peptide repeats, Ran-GTP binding sites, zinc fingers, a cyclophilin A homologous domain, and a leucine-rich region. J. Biol. Chem. 270: 14209-14213, 1995. [PubMed: 7775481] [Full Text: https://doi.org/10.1074/jbc.270.23.14209]
Yokoyama, N., Hayashi, N., Seki, T., Pante, N., Ohba, T., Nishii, K., Kuma, K., Hayashida, T., Miyata, T., Abei, U., Fukui, M., Nishimoto, T. A giant nucleopore protein that binds Ran/TC4. Nature 376: 184-188, 1995. [PubMed: 7603572] [Full Text: https://doi.org/10.1038/376184a0]