OTUB1 is a 271 amino acid protein that contains one OTU (ovarian tumor) domain and belongs to the OTU family of predicted cysteine proteases. Expressed as two isoforms (one of which is present throughout the body and the other of which is present only in lymphoid tissues), OTUB1 functions as a hydrolase that can remove ubiquitin residues from target proteins, thereby preventing protein degradation and playing an important role in protein turnover. OTUB1 interacts with GRAIL and, via this interaction, plays a role in the regulation and the induction of T-cell anergy, a phenomenon that occurs when T-cells are rendered unresponsive to their cognate antigens. Due to its interaction with GRAIL, OTUB1 is an important regulator of immune responses in secondary lymphoid organs.
Function:
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 that increases affinity for UBE2N/UBC13 and disrupts interaction with UBE2V1. The OTUB1-UBE2N/UBC13-free ubiquitin complex adopts a configuration that mimics a cleaved 'Lys48'-linked di-ubiquitin chain.
Subunit:
Isoform 1 and isoform 2 interact with RNF128. Isoform 1 forms a ternary complex with RNF128 and USP8. Isoform 1 interacts with the SLCterminal UCH catalytic domain of USP8. Isoform 2 does not associate with USP8. Interacts with FUS, ESR1 and GNB2L1/RACK1. Interacts with UBE2N/UBC13.
Subcellular Location:
Cytoplasm.
Tissue Specificity:
Isoform 1 is ubiquitous. Isoform 2 is expressed only in lymphoid tissues such as tonsils, lymph nodes and spleen, as well as peripheral blood mononuclear cells.
Similarity:
Belongs to the peptidase C65 family.
Contains 1 OTU domain.
SWISS:
Q96FW1
Gene ID:
55611
Database links:
Entrez Gene: 55611 Human
Entrez Gene: 107260 Mouse
Entrez Gene: 293705 Rat
Omim: 608337 Human
SwissProt: Q96FW1 Human
SwissProt: Q7TQI3 Mouse
SwissProt: B2RYG6 Rat
Unigene: 473788 Human
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