Alternative titles; symbols
HGNC Approved Gene Symbol: UBB
Cytogenetic location: 17p11.2 Genomic coordinates (GRCh38): 17:16,380,779-16,382,745 (from NCBI)
Ubiquitin, a small protein consisting of 76 amino acids, has been found in all eukaryotic cells studied. It is one of the most conserved proteins known; the amino acid sequence is identical from insects to humans, and there are only 3 substitutions within the plant and yeast sequences. Two classes of ubiquitin genes are recognized. Class I is a polyubiquitin gene, such as UBB or UBC (191340), encoding a polyprotein of tandemly repeated ubiquitins. The class II genes are fusion products between a single ubiquitin gene and 1 of 2 other possible sequences, either 52 or 76 to 80 predominantly basic amino acids (see UBA52, 191321, and UBA80, 191343, respectively). Ubiquitin is required for ATP-dependent, nonlysosomal intracellular protein degradation, which eliminates most intracellular defective problems as well as normal proteins with a rapid turnover. Degradation involves covalent binding of ubiquitin to the protein to be degraded, through isopeptide bonds from the C-terminal glycine residue to the epsilon-amino groups of lysyl side chains. Presumably, the function of ubiquitin is to label the protein for disposal by intracellular proteases. The most abundant ubiquitin-protein conjugate, however, is ubiquitin-H2A, in which ubiquitin is bound to lys119 in histone H2A; this conjugate is not degraded. Since such ubiquitinated histones are present primarily in actively transcribed chromosomal regions, ubiquitin may play a role in regulation of gene expression (summary by Wiborg et al. (1985) and Baker and Board (1987)).
Wiborg et al. (1985) determined that ubiquitin is encoded as a multigene family.
Baker and Board (1987) studied cDNA and genomic clones of ubiquitin.
By in situ hybridization, Webb et al. (1990) assigned the 3-coding unit polyubiquitin gene UBB and its nonprocessed pseudogene to chromosome 17p12-p11.1.
Finley et al. (1989) demonstrated that the basic amino acids fused to ubiquitin in the class II gene products represent ribosomal proteins, and that their fusion to ubiquitin performs a crucial role in ribosome biogenesis in the Saccharomyces cerevisiae. Redman and Rechsteiner (1989) studied these 3-prime in-frame extensions of the ubiquitin genes in mammalian systems and concluded, as did Finley et al. (1989), that the C-terminal extension proteins are ribosomal components.
Sutovsky et al. (1999) demonstrated that sperm mitochondria are selectively marked for destruction by a ubiquitin tag. In fertilized eggs from rhesus monkeys and cows the ubiquitination was evident at first mitosis. The signal typically disappeared between the 4-cell and the 8-cell stages of development. This ubiquitination also occurs in the male reproductive tract, but the ubiquitinated sites are masked by disulfide bonds during passage through the epididymis.
Conaway et al. (2002) reviewed the role of ubiquitin in transcription regulation in both proteasome-dependent and proteasome-independent mechanisms.
Cui et al. (2010) showed that Cif homolog from Burkholderia pseudomallei (CHBP) was a potent inhibitor of the eukaryotic ubiquitination pathway in human cells. CHBP acted as a deamidase that specifically and efficiently deamidated gln40 in ubiquitin and ubiquitin-like protein NEDD8 (603171) both in vitro and during Burkholderia infection. Deamidated ubiquitin was impaired in supporting ubiquitin-chain synthesis. Cif selectively deamidated NEDD8, which abolished the activity of neddylated Cullin-RING ubiquitin ligases (CRLs). Ubiquitination and ubiquitin-dependent degradation of multiple CRL substrates were impaired by Cif in enteropathogenic E. coli (EPEC)-infected cells. Mutations of substrate-contacting residues in Cif abolished or attenuated EPEC-induced cytopathic phenotypes of cell cycle arrest and actin stress fiber formation.
Association of Ubiquitin With Disease
Lowe et al. (1988) discussed the role of ubiquitin in a variety of neuropathologic conditions including Parkinson disease (see 168600), Pick disease (see 172700), and Alzheimer disease (AD; 104300).
The protein deposits in neurofibrillary tangles, neuritic plaques, and neuropil threads in the cerebral cortex of patients with Alzheimer disease and Down syndrome (DS; 190685) contain forms of beta-amyloid precursor protein (APP; 104760) and ubiquitin-B that are aberrant in the C terminus. Based on studies of homozygous Brattleboro rats with diabetes insipidus who show a GA deletion in a GAGAG motif in mRNA transcripts of the vasopressin gene (192340), van Leeuwen et al. (1998) postulated that a dinucleotide deletion (delta-GA, delta-GT, or delta-CT) could occur in mRNA transcripts as a consequence of aging. The authors found GAGAG motifs in UBB mRNA, and predicted that a +1 frameshift in APP (APP+1) or UBB (UBB+1) would result in a protein with an aberrant C terminus, lacking the glycine residue essential for multiubiquitylation. Immunoreactivity to UBB+1 and APP+1 was found in brains from patients with early- and late-onset AD and Down syndrome. The aberrant UBB+1 and APP+1 proteins were not found in young control subjects but were present in elderly control patients. The aberrant proteins were not found in patients with Parkinson disease. Van Leeuwen et al. (1998) stated that the process is probably not limited to postmitotic cells; however, postmitotic neurons are less capable of compensating for transcript-modifying activity and are thus particularly sensitive to the accumulation of frameshifted proteins. Thus, during aging, single neurons may generate and accumulate abnormal proteins, leading to cellular disturbances and causing degeneration.
Van Leeuwen et al. (2006) found that the aberrant APP+1 protein was present in neurons with beaded fibers in young individuals with Down syndrome in the absence of any pathologic hallmarks of AD. Both APP+1 and UBB+1 were present within brain neurofibrillary tangles and neuritic plaques from older DS patients and patients with various forms of autosomal dominant AD. Moreover, APP+1 and UBB+1 were detected in the neuropathologic hallmarks of other tau (MAPT; 157140)-related dementias, including Pick disease (172700), progressive supranuclear palsy (PSP; 601104), and less commonly frontotemporal dementia (FTD; 600274). Van Leeuwen et al. (2006) postulated that accumulation of APP+1 and UBB+1 contributes to various forms of dementia.
Fratta et al. (2004) found that 70 to 80% of the vacuolated muscle fibers in samples from 10 patients with sporadic inclusion body myositis (147421) contained strong immunoreactivity to mutant ubiquitin (UBB+1) in the form of numerous well-defined plaque-like, dotted, or elongated aggregates. Similar aggregates were identified in 10 to 15% of the nonvacuolated normal-appearing fibers. In the abnormal fibers, these aggregates were concurrently immunoreactive for wildtype UBB and either beta-amyloid or phosphorylated tau (MAPT; 157140). None of the control biopsies were immunoreactive to UBB+1. Fratta et al. (2004) suggested that the UBB+1-inhibited proteasome cannot properly degrade toxic proteins, resulting in their accumulation and aggregation.
Tank and True (2009) expressed a protein analogous to UBB+1 in yeast (Ubb(ext)) and demonstrated that it impaired the ubiquitin/proteasome system. Ubb(ext) did not cause protein aggregation itself, but it rendered yeast more susceptible to other toxic protein aggregates. Ubb(ext) appeared to act as a modifier that altered substrate ubiquitination and the function of the ubiquitin/proteasome system.
Smith-Magenis syndrome (SMS; 182290) is a syndrome exhibiting multiple congenital anomalies and mental retardation, with distinctive behavioral characteristics, sleep disturbance, and dysmorphic features, associated with a heterozygous interstitial deletion of 17p11.2. Heterozygous frameshift mutations of the RAI1 gene (607642) seem to be responsible for most of the SMS features, but other deleted genes in the SMS region may modify the overall phenotype. In a comparative genome hybridization analysis of the short arm of chromosome 17 in 30 patients with SMS, Andrieux et al. (2007) found that 3 had large deletions and that 2 of these had cleft palate, which was not found in any of the other patients. The smallest extra-deleted region associated with cleft palate and SMS was 1.4 Mb, contained less than 16 genes, and was located at 17p12-p11.2. Gene expression array data showed that the UBB gene is significantly expressed in the first branchial arch in the fourth and fifth weeks of human development. Together, the data supported UBB as a candidate gene for isolated cleft palate.
Ryu et al. (2008) found that newborn Ubb-null mice were smaller than wildtype or heterozygous littermates and exhibited subtle perinatal linear growth retardation, but they were otherwise indistinguishable from wildtype mice. However, Ubb deletion led to adult-onset obesity that strongly correlated with selective degeneration of neurons that control energy balance in the arcuate nucleus of the hypothalamus. Total Ub levels were reduced in the hypothalamus of Ubb-null mice. Ryu et al. (2008) concluded that adequate cellular UB is essential for neuronal survival.
Andrieux, J., Villenet, C., Quief, S., Lignon, S., Geffroy, S., Roumier, C., de Leersnyder, H., de Blois, M.-C., Manouvrier, S., Delobel, B., Benzacken, B., Bitoun, P., Attie-Bitach, T., Thomas, S., Lyonnet, S., Vekemans, M., Kerckaert, J.-P. Genotype-phenotype correlation of 30 patients with Smith-Magenis syndrome (SMS) using comparative genome hybridisation array: cleft palate in SMS is associated with larger deletions. (Letter) J. Med. Genet. 44: 537-540, 2007. [PubMed: 17468296] [Full Text: https://doi.org/10.1136/jmg.2006.048736]
Baker, R. T., Board, P. G. The human ubiquitin gene family: structure of a gene and pseudogenes from the Ub B subfamily. Nucleic Acids Res. 15: 443-463, 1987. [PubMed: 3029682] [Full Text: https://doi.org/10.1093/nar/15.2.443]
Conaway, R. C., Brower, C. S., Conaway, J. W. Emerging roles of ubiquitin in transcription regulation. Science 296: 1254-1258, 2002. [PubMed: 12016299] [Full Text: https://doi.org/10.1126/science.1067466]
Cui, J., Yao, Q., Li, S., Ding, X., Lu, Q., Mao, H., Liu, L., Zheng, N., Chen, S., Shao, F. Glutamine deamidation and dysfunction of ubiquitin/NEDD8 induced by a bacterial effector family. Science 329: 1215-1218, 2010. [PubMed: 20688984] [Full Text: https://doi.org/10.1126/science.1193844]
Ecker, D. J., Butt, T. R., Marsh, J., Sternberg, E. J., Margolis, N., Monia, B. P., Jonnalagadda, S., Khan, M. I., Weber, P. L., Mueller, L., Crooke, S. T. Gene synthesis, expression, structures, and functional activities of site-specific mutants of ubiquitin. J. Biol. Chem. 262: 14213-14221, 1987. [PubMed: 2820997]
Finley, D., Bartel, B., Varshavsky, A. The tails of ubiquitin precursors are ribosomal proteins whose fusion to ubiquitin facilitates ribosome biogenesis. Nature 338: 394-401, 1989. [PubMed: 2538753] [Full Text: https://doi.org/10.1038/338394a0]
Fratta, P., Engel, W. K., Van Leeuwen, F. W., Hol, E. M., Vattemi, G., Askanas, V. Mutant ubiquitin UBB+1 is accumulated in sporadic inclusion-body myositis muscle fibers. Neurology 63: 1114-1117, 2004. [PubMed: 15452314] [Full Text: https://doi.org/10.1212/01.wnl.0000138574.56908.5d]
Lowe, J., Blanchard, A., Morrell, K., Lennox, G., Reynolds, L., Billett, M., Landon, M., Mayer, R. J. Ubiquitin is a common factor in intermediate filament inclusion bodies of diverse type in man, including those of Parkinson's disease, Pick's disease, and Alzheimer's disease, as well as Rosenthal fibres in cerebellar astrocytomas, cytoplasmic bodies in muscle, and Mallory bodies in alcoholic liver disease. J. Path. 155: 9-15, 1988. [PubMed: 2837558] [Full Text: https://doi.org/10.1002/path.1711550105]
Redman, K. L., Rechsteiner, M. Identification of the long ubiquitin extension as ribosomal protein S27a. Nature 338: 438-440, 1989. [PubMed: 2538756] [Full Text: https://doi.org/10.1038/338438a0]
Ryu, K.-Y., Garza, J. C., Lu, X.-Y., Barsh, G. S., Kopito, R. R. Hypothalamic neurodegeneration and adult-onset obesity in mice lacking the Ubb polyubiquitin gene. Proc. Nat. Acad. Sci. 105: 4016-4021, 2008. [PubMed: 18299572] [Full Text: https://doi.org/10.1073/pnas.0800096105]
Sutovsky, P., Moreno, R. D., Ramalho-Santos, J., Dominko, T., Simerly, C., Schatten, G. Ubiquitin tag for sperm mitochondria. Nature 402: 371-372, 1999. [PubMed: 10586873] [Full Text: https://doi.org/10.1038/46466]
Tank, E. M. H., True, H. L. Disease-associated mutant ubiquitin causes proteasomal impairment and enhances the toxicity of protein aggregates. PLoS Genet. 5: e1000382 only, 2009. Note: Electronic Article. [PubMed: 19214209] [Full Text: https://doi.org/10.1371/journal.pgen.1000382]
van Leeuwen, F. W., de Kleijn, D. P. V., van den Hurk, H. H., Neubauer, A., Sonnemans, M. A. F., Sluijs, J. A., Koycu, S., Ramdjielal, R. D. J., Salehi, A., Martens, G. J. M., Grosveld, F. G., Burbach, J. P. H., Hol, E. M. Frameshift mutants of beta-amyloid precursor protein and ubiquitin-B in Alzheimer's and Down patients. Science 279: 242-247, 1998. [PubMed: 9422699] [Full Text: https://doi.org/10.1126/science.279.5348.242]
van Leeuwen, F. W., van Tijn, P., Sonnemans, M. A. F., Hobo, B., Mann, D. M. A., Van Broeckhoven, C., Kumar-Singh, S., Cras, P., Leuba, G., Savioz, A., Maat-Schieman, M. L. C., Yamaguchi, H., Kros, J. M., Kamphorst, W., Hol, E. M., de Vos, R. A. I., Fischer, D. F. Frameshift proteins in autosomal dominant forms of Alzheimer disease and other tauopathies. Neurology 66 (suppl. 1): S86-S92, 2006. [PubMed: 16432153] [Full Text: https://doi.org/10.1212/01.wnl.0000193882.46003.6d]
Webb, G. C., Baker, R. T., Fagan, K., Board, P. G. Localization of the human UbB polyubiquitin gene to chromosome band 17p11.1-17p12. Am. J. Hum. Genet. 46: 308-315, 1990. [PubMed: 2154095]
Wiborg, O., Pedersen, M. S., Wind, A., Berglund, L. E., Marcker, K. A., Vuust, J. The human ubiquitin multigene family: some genes contain multiple directly repeated ubiquitin coding sequences. EMBO J. 4: 755-759, 1985. [PubMed: 2988935] [Full Text: https://doi.org/10.1002/j.1460-2075.1985.tb03693.x]