Alternative titles; symbols
HGNC Approved Gene Symbol: UBR4
Cytogenetic location: 1p36.13 Genomic coordinates (GRCh38): 1:19,074,510-19,210,266 (from NCBI)
UBR4 is an E3 ligase that plays a role in the N-end rule pathway and helps degrade aggregation-prone nascent polypeptides. UBR3 forms an E3 ligase complex with KCMF1 (614719) and calmodulin (see CALM1, 114180) that functions to turn off the mitochondrial stress response after the event is resolved (Haakonsen et al., 2024).
By sequencing clones obtained from a size-fractionated fetal brain cDNA library, Nagase et al. (2000) cloned RBAF600, which they designated KIAA1307. RT-PCR ELISA detected BBAF600 in all adult and fetal tissues and specific brain regions examined. Highest expression was in cerebellum and caudate nucleus.
By mass spectrometric analysis of proteins associated with retinoblastoma protein (RB1; 614041) in HeLa cells, followed by peptide sequencing, EST database analysis, and screening a cDNA library, Nakatani et al. (2005) cloned RBAF600, which they designated p600. The deduced 5,183-amino acid protein has a calculated molecular mass of 573.5 kD. Immunostaining of human foreskin fibroblasts localized p600 in a continuous meshwork pattern from the nucleus to the cytoplasm, passing through the nuclear envelope. In the cytoplasm, p600 was concentrated at the leading edge of membrane structures.
The human papillomavirus (HPV) type 16 E7 gene encodes a multifunctional oncoprotein that can subvert multiple cellular regulatory pathways. E7 targets RB and the related pocket proteins p107 (RBL1; 116957) and p130 (RBL2; 180203). By tandem affinity purification in the HPV-positive HeLa cell cervical carcinoma cell line and mass spectrometry, Huh et al. (2005) found that p600 is a cellular target of E7. The association of E7 with p600 was independent of the pocket proteins and was mediated through the N-terminal E7 domain. Huh et al. (2005) observed that depletion of p600 by RNA interference substantially decreased anchorage-independent growth in HPV-positive and -negative human cancer cells. They concluded that p600 is a cellular target of E7 that regulates cellular pathways that contribute to anchorage-independent growth and cellular transformation.
Nakatani et al. (2005) found that RBAF600 associates with RB in the nucleus and with Ca(2+)-bound calmodulin in the cytoplasm. They noted that in the nucleus, p600 and RB appears to act as a chromatin scaffold, and in the cytoplasm p600 and clathrin (see CLTC, 118955) form a meshwork structure which could contribute to cytoskeletal organization and membrane morphogenesis. Reduced expression of p600 with interfering RNA abrogated integrin (see ITGB1, 135630)-mediated ruffled membrane formation and prevented activation of integrin-mediated survival pathways. Knockdown of p600 sensitized cells to apoptosis induced by cell detachment.
By knockout analysis in HEK293T cells, Haakonsen et al. (2024) demonstrated that UBR4 was important when mitochondrial function was compromised. UBR4 bound KCMF1 and calmodulin to form an E3 ligase complex that sustained survival of cells undergoing mitochondrial import stress. The authors named the UBR4-KCMF1-calmodulin complex 'silencing factor of the integrated stress response,' or SIFI. SIFI targeted HRI (613635) and the cytosolic cleavage fragment of DELE1 (615741) (cDELE1), proteins that actively mediate the cellular response to mitochondrial import stress, to promote their ubiquitylation and degradation to silence the integrated stress response in cells. The N terminus of HRI contains 2 alpha helices that served as degrons, with each capable of mediating recognition by SIFI. Multiple motifs in cDELE1, including an N-terminal motif that was exposed after cleavage and a helix with similarity to HRI degrons, were recognized by SIFI. The helical HRI and cDELE1 degrons closely resembled mitochondrial presequences. Consequently, SIFI not only recognized and targeted HRI and cDELE1, but it also appeared to target other proteins containing a presequence, including unimported mitochondrial proteins that accumulated in the cytoplasm during import stress, for their ubiquitylation and degradation. Ubiquitylation of presequences depended on the calmodulin and KCMF1 subunits of SIFI. These mitochondrial presequences and cDELE1 and HRI degrons, which were similar to stress response degrons, were related bifunctional motifs that could be recognized by both the mitochondrial import machinery and SIFI. Consequently, these converging degrons were able to couple stress resolution to stress response silencing in cells. Further analysis revealed that HRI and DELE1 mediated stress response signaling without affecting mitochondrial protein import, and pharmacologic silencing of the stress response restored survival of UBR4- or KCMF1-knockout cells that failed to resolve mitochondrial stress.
By radiation hybrid analysis, Nagase et al. (2000) mapped the RBAF600 gene to chromosome 1.
Gross (2014) mapped the UBR4 gene to chromosome 1p36.13 based on an alignment of the UBR4 sequence (GenBank AF348492) with the genomic sequence (GRCh38).
Associations Pending Confirmation
For discussion of a possible association between variation in the UBR4 gene and episodic ataxia-8 (EA8; 616055), see 609890.0001.
Monies et al. (2017) reported 2 unrelated Saudi Arabian adults with neurologic abnormalities associated with heterozygous missense variants in the UBR4 gene identified through whole-exome sequencing. The patients were part of a large cohort of 1,000 Saudi families with suspected Mendelian disorders who underwent whole-exome sequencing. Clinical details were limited. Patient 16-2737 was a 32-year-old woman with developmental regression, ataxia, and brain atrophy who carried a heterozygous c.2873C-A transversion (NM_020765) in exon 22 that resulted in an S958Y variant. Patient 16-2768 was a 41-year-old man with adult onset of behavioral changes progressing to dementia, seizures, and white matter abnormalities on brain imaging, with a positive family history, who carried a heterozygous c.9787G-A transition in exon 66 that resulted in an A3263T variant. Functional studies of the variants and studies of patient cells were not performed.
Choi et al. (2017) reported 2 unrelated individuals with sporadic episodic ataxia associated with heterozygous missense variants in the UBR4 gene identified through whole-exome sequencing. The patients were part of a cohort of 39 Korean patients with episodic ataxia who underwent whole-exome sequencing. Clinical details were limited. P26 was a 54-year-old woman with onset of features at age 53 and gaze-evoked nystagmus who carried a c.15125C-T transition (NM_020765.2) in exon 103 that resulted in an A5042V variant. Hamosh (2024) noted that the A5042V variant was present in 20 of 1,614,008 total alleles in the gnomAD database (v4.0), in heterozygosity only, for an allele frequency of 0.00001239, and in 15 of 44,842 East Asian alleles, for an allele frequency of 0.0003345. P28 was a 52-year-old woman with onset of symptoms at age 49 who carried a c.7742C-T transition in exon 52 that resulted in an A2581V variant. Hamosh (2024) noted that the A2581V variant was not present in the gnomAD database (v4.0). Neither individual had a family history of the disorder, but de novo occurrence could not be confirmed. Two additional probands with a family history of episodic ataxia carried variants in both the UBR4 and CACNA1A genes (601011). Functional studies of the variants and studies of patient cells were not performed.
This variant is classified as a variant of unknown significance because its contribution to episodic ataxia-8 (EA8; 616055) has not been confirmed.
In affected members of a large Irish family with autosomal dominant episodic ataxia-8, Conroy et al. (2014) identified a C-to-T transition in the UBR4 gene, resulting in an arg5091-to-his (R5091H) substitution. The variant, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in the 1000 Genomes Project or Exome Sequencing Project databases, or in 38 in-house Irish exomes. Functional studies of the variant were not performed, but Conroy et al. (2014) noted that the UBR4 gene is thought to play a role in calcium signaling and thus may be involved in the regulation of neuronal excitability.
Choi, K.-D., Kim, J.-S., Kim, H.-J., Jung, I., Jeong, S.-H., Lee, S.-H., Kim, D. U., Kim, S.-H., Choi, S. Y., Shin, J.-H., Kim, D.-S., Park, K.-P., Kim, H.-S., Choi, J.-H. Genetic variants associated with episodic ataxia in Korea. Sci. Rep. 7: 13855, 2017. [PubMed: 29062094] [Full Text: https://doi.org/10.1038/s41598-017-14254-7]
Conroy, J., McGettigan, P., Murphy, R., Webb, D., Murphy, S. M., McCoy, B., Albertyn, C., McCreary, D., McDonagh, C., Walsh, O., Lynch, S., Ennis, S. A novel locus for episodic ataxia:UBR4 the likely candidate. Europ. J. Hum. Genet. 22: 505-510, 2014. [PubMed: 23982692] [Full Text: https://doi.org/10.1038/ejhg.2013.173]
Gross, M. B. Personal Communication. Baltimore, Md. 10/21/2014.
Haakonsen, D. L., Heider, M., Ingersoll, A. J., Vodehnal, K., Witus, S. R., Uenaka, T., Wernig, M., Rape, M. Stress response silencing by an E3 ligase mutated in neurodegeneration. Nature 626: 874-880, 2024. [PubMed: 38297121] [Full Text: https://doi.org/10.1038/s41586-023-06985-7]
Hamosh, A. Personal Communication. Baltimore, Md. 03/29/2024.
Huh, K.-W., DeMasi, J., Ogawa, H., Nakatani, Y., Howley, P. M., Munger, K. Association of the human papillomavirus type 16 E7 oncoprotein with the 600-kDa retinoblastoma protein-associated factor, p600. Proc. Nat. Acad. Sci. 102: 11492-11497, 2005. [PubMed: 16061792] [Full Text: https://doi.org/10.1073/pnas.0505337102]
Monies, D., Abouelhoda, M., AlSayed, M., Alhassnan, Z., Alotaibi, M., Kayyali, H., Al-Owain, M., Shah, A., Rahbeeni, Z., Al-Muhaizea, M. A., Alzaidan, H. I., Cupler, E., and 95 others. The landscape of genetic diseases in Saudi Arabia based on the first 1000 diagnostic panels and exomes. Hum. Genet. 136: 921-939, 2017. [PubMed: 28600779] [Full Text: https://doi.org/10.1007/s00439-017-1821-8]
Nagase, T., Kikuno, R., Ishikawa, K., Hirosawa, M., Ohara, O. Prediction of the coding sequences of unidentified human genes. XVI. The complete sequences of 150 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 7: 65-73, 2000. [PubMed: 10718198] [Full Text: https://doi.org/10.1093/dnares/7.1.65]
Nakatani, Y., Konishi, H., Vassilev, A., Kurooka, H., Ishiguro, K., Sawada, J., Ikura, T., Korsmeyer, S. J., Qin, J., Herlitz, A. M. p600, a unique protein required for membrane morphogenesis and cell survival. Proc. Nat. Acad. Sci. 102: 15093-15098, 2005. Note: Erratum: Proc. Nat. Acad. Sci. 102: 17882 only, 2005. [PubMed: 16214886] [Full Text: https://doi.org/10.1073/pnas.0507458102]