Ubiquitin thioesterase OTUB1 (OTUB1)
The protein contains 271 amino acids for an estimated molecular weight of 31284 Da.
Hydrolase that can specifically remove 'Lys-48'-linked conjugated ubiquitin from proteins and plays an important regulatory role at the level of protein turnover by preventing degradation. Regulator of T-cell anergy, a phenomenon that occurs when T-cells are rendered unresponsive to antigen rechallenge and no longer respond to their cognate antigen. Acts via its interaction with RNF128/GRAIL, a crucial inductor of CD4 T-cell anergy. Isoform 1 destabilizes RNF128, leading to prevent anergy. In contrast, isoform 2 stabilizes RNF128 and promotes anergy. Surprisingly, it regulates RNF128-mediated ubiquitination, but does not deubiquitinate polyubiquitinated RNF128. Deubiquitinates estrogen receptor alpha (ESR1). Mediates deubiquitination of 'Lys-48'-linked polyubiquitin chains, but not 'Lys-63'-linked polyubiquitin chains. Not able to cleave di-ubiquitin. Also capable of removing NEDD8 from NEDD8 conjugates, but with a much lower preference compared to 'Lys-48'-linked ubiquitin.Plays a key non-catalytic role in DNA repair regulation by inhibiting activity of RNF168, an E3 ubiquitin-protein ligase that promotes accumulation of 'Lys-63'-linked histone H2A and H2AX at DNA damage sites. Inhibits RNF168 independently of ubiquitin thioesterase activity by binding and inhibiting UBE2N/UBC13, the E2 partner of RNF168, thereby limiting spreading of 'Lys-63'-linked histone H2A and H2AX marks. Inhibition occurs by binding to free ubiquitin: free ubiquitin acts as an allosteric regulator th (updated: March 4, 2015)
Protein identification was indicated in the following studies:
- Goodman and co-workers. (2013) The proteomics and interactomics of human erythrocytes. Exp Biol Med (Maywood) 238(5), 509-518.
- Lange and co-workers. (2014) Annotating N termini for the human proteome project: N termini and Nα-acetylation status differentiate stable cleaved protein species from degradation remnants in the human erythrocyte proteome. J Proteome Res. 13(4), 2028-2044.
- Hegedűs and co-workers. (2015) Inconsistencies in the red blood cell membrane proteome analysis: generation of a database for research and diagnostic applications. Database (Oxford) 1-8.
- D'Alessandro and co-workers. (2017) Red blood cell proteomics update: is there more to discover? Blood Transfus. 15(2), 182-187.
- Bryk and co-workers. (2017) Quantitative Analysis of Human Red Blood Cell Proteome. J Proteome Res. 16(8), 2752-2761.
Methods
The following articles were analysed to gather the proteome content of erythrocytes.
The gene or protein list provided in the studies were processed using the ID mapping API of Uniprot in September 2018. The number of proteins identified and mapped without ambiguity in these studies is indicated below.
Only Swiss-Prot entries (reviewed) were considered for protein evidence assignation.
| Publication | Identification 1 | Uniprot mapping 2 | Not mapped / Obsolete | TrEMBL | Swiss-Prot |
|---|---|---|---|---|---|
| Goodman (2013) | 2289 (gene list) | 2278 | 53 | 20599 | 2269 |
| Lange (2014) | 1234 | 1234 | 7 | 28 | 1224 |
| Hegedus (2015) | 2638 | 2622 | 0 | 235 | 2387 |
| Wilson (2016) | 1658 | 1528 | 170 | 291 | 1068 |
| d'Alessandro (2017) | 1826 | 1817 | 2 | 0 | 1815 |
| Bryk (2017) | 2090 | 2060 | 10 | 108 | 1942 |
| Chu (2018) | 1853 | 1804 | 55 | 362 | 1387 |
1 as available in the article and/or in supplementary material
2 uniprot mapping returns all protein isoforms as one entry
The compilation of older studies can be retrieved from the Red Blood Cell Collection database.
The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.
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Biological Process
Adaptive immune response
Cellular response to DNA damage stimulus
Cellular response to interleukin-1
DNA repair
Immune system process
Negative regulation of double-strand break repair
Negative regulation of histone H2A K63-linked ubiquitination
Protein deubiquitination
Protein K48-linked deubiquitination
The reference OMIM entry for this protein is 608337
Otu domain-containing ubiquitin aldehyde-binding protein 1; otub1
Otu domain-containing ubal-binding protein 1
Otubain 1; otu1; otb1
DESCRIPTION
Otubains, such as OTB1, are deubiquitylating cysteine proteases (DUBs; see 602519) that belong to the ovarian tumor (OTU) protein superfamily. Like other DUBs, otubains cleave proteins precisely at the ubiquitin (UB; see 191339)-protein bond (Balakirev et al., 2003).CLONING
By affinity purification of DUBs from HeLa cells using UB aldehyde (UBAL), followed by SDS-PAGE and mass spectrophotometric analysis, Balakirev et al. (2003) obtained cDNAs encoding OTB1 and OTB2 (608338). The 271-amino acid, 31-kD OTB1 protein contains UB-interaction motifs (UIMs) and UB-associated (UBA) domains, as well as putative nuclear localization signals and a consensus LxxLL motif. RT-PCR and Western blot analyses revealed wide expression of OTB1, with 2 isoforms in leukocytes. By PCR and immunoblot analysis, Soares et al. (2004) identified an 815-bp OTB1 isoform, which was expressed ubiquitously, and a 950-bp isoform, which was expressed only in lymphoid tissue. The 815-bp isoform encodes the 31-kD protein reported by Balakirev et al. (2003), whereas the 950-bp isoform encodes a 35-kD, 315-amino acid protein, OTB1ARF1 (OTB1 alternative reading frame-1), that lacks the asp and cys residues in the OTU cysteine proteinase catalytic core and retains only the C-terminal flanking region of the OTU domain. The OTB1ARF1 transcript is produced from the same transcription start site as OTB1 but uses an AUG codon located in exon 2 and in a different reading frame from that of OTB1. In addition, there is no splicing between exons 4 and 5 in OTB1ARF1, which causes a frameshift back to the same reading frame as OTB1.GENE FUNCTION
By yeast 2-hybrid analysis, Soares et al. (2004) showed that GRAIL (RNF128; 300439) binds to OTB1. Although OTB1 was found to have DUB activity, it failed to deubiquitinate polyubiquitinated GRAIL. Immunoprecipitation and coexpression analysis indicated that OTB1, but not OTB1ARF1, binds to the C-terminal UCH catalytic domain of USP8 (603158) in a trimolecular complex with GRAIL. Soares et al. (2004) studied cells from T-cell receptor-transgenic mice expressing the alternative forms of OTB1. OTB1-expressing cells contained negligible amounts of Grail, proliferated well, and produced large amounts of interleukin-2 (IL2; 147680) after antigenic stimulation. In contrast, cells expressing OTB1ARF1 contained large amounts of Grail and were functionally anergic, proliferating poorly and not producing Il2. Soares et al. (2004) concluded that the balance of OTB1 and OTB1ARF1 in T cells is an important factor that regulates GRAIL stability and the outcome of immune responses in secondary lymphoid organs. Nakada et al. (2010) reported that OTUB1, a deubiquitinating enzyme, is an inhibitor of double stranded break induced chromatin ubiquitination. Surprisingly, they found that OTUB1 suppresses RNF168 (612688)-dependent polyubiquitination independently of its catalytic activity. OTUB1 does so by binding to and inhibiting UBC13 (UBE2N; 603679), the cognate E2 enzyme for RNF168. Nakada et al. (2010) suggested that this unusual mode of regulation is unlikely to be limited to UBC13 because analysis of OTUB1-associated proteins revealed that OTUB1 binds to E2s of the UBE2D and UBE2E subfamilies. Finally, OTUB1 depletion mitigates the double-stranded break repair defect associated with defective ATM (607585) signaling, indicating that pharmacologic targeting of the OTUB1-UBC13 interaction might enhance the DNA damage ... More on the omim web site
Feb. 2, 2018: Protein entry updated
Automatic update: Uniprot description updated
Dec. 19, 2017: Protein entry updated
Automatic update: Uniprot description updated
March 16, 2016: Protein entry updated
Automatic update: OMIM entry 608337 was added.
Jan. 28, 2016: Protein entry updated
Automatic update: model status changed
Jan. 25, 2016: Protein entry updated
Automatic update: model status changed