ubiquitin thioesterase OTUB1; deubiquitinating enzyme OTUB1; OTU domain-containing ubiquitin aldehyde-binding protein 1; otubain-1; hOTU1; ubiquitin-specific-processing protease OTUB1 (OTUB1, OTB1, OTU1, HSPC263)

Function

• hydrolase that can remove conjugated ubiquitin from proteins
• regulatory role at the level of protein turnover by preventing degradation
• regulator of T-cell anergy
• acts via its interaction with RNF128/GRAIL, an inducer of CD4 T-cell anergy
• isoform 1 destabilizes RNF128 inhibiting anergy
• in contrast, isoform 2 stabilizes RNF128 & promotes anergy
• surprisingly, OTUB1 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 nuch lower preference compared to Lys-48-linked ubiquitin
• thiol-dependent hydrolysis of ester, thioester, amide, peptide & isopeptide bonds formed by the C-terminal Gly of ubiquitin
• isoform 1 & isoform 2 interact with RNF128
• isoform 1 forms a ternary complex with RNF128 & USP8
• isoform 1 interacts with the C-terminal UCH catalytic domain of USP8
• isoform 2 does not associate with USP8
• interacts with FUS, ESR1 & GNB2L1/RACK1

Structure

• addition to ubiquitin-binding at the Cys-91 active site, a proximal ubiquitin-binding site is also present at Cys-23
• occupancy of the active site is needed to enable tight binding to the second site
• distinct binding sites for the ubiquitins may allow discrimination among different isopeptide linkages (i.e Lys-48-, Lys-63-linked polyubiquitin) in polyubiquitin substrates & achieve linkage-specific deubiquitination
• belongs to the peptidase C65 family
• contains 1 OTU domain

Compartment

cytoplasm (putative)

Alternative splicing

• named isoforms=2

Expression

• isoform 1 is ubiquitous
• isoform 2 is expressed only in lymphoid tissues including tonsils, lymph nodes & spleen, as well as in peripheral blood mononuclear cells

Notes

• the His-265 active site of the catalytic triad may be too far to interact directly with the active site Cys-91
• OTUB1 may be in an inactive conformation in absence of ubiquitin & a conformation change may move His-265 in the proximity of Cys-91 in presence of ubiquitin substrate

More general terms

• ubiquitin C-terminal hydrolase
• phosphoprotein

Database

• Entrez gene: http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=55611
• Kegg: http://www.genome.jp/dbget-bin/www_bget?hsa:55611
• OMIM: https://mirror.omim.org/entry/608337
• UniProt: http://www.uniprot.org/uniprot/Q96FW1.html