Ubiquitin thioesterase OTUB1

OTUB1 (ubiquitin thioesterase OTUB1) is a deubiquitinating enzyme that removes Lys-48-linked conjugated ubiquitin from proteins, thereby regulating protein turnover and preventing degradation (UniProt: Q96FW1). Beyond its catalytic role, OTUB1 acts as a non-catalytic regulator of DNA repair by inhibiting RNF168 activity and serves as a modulator of mTORC1 and mTORC2 complexes through interactions with E2 enzymes and substrate proteins such as RPTOR and DEPTOR (UniProt: Q96FW1). The protein also regulates T-cell anergy through its interaction with RNF128/GRAIL.

In Alzheimer's Disease, OTUB1 shows an ambiguous regulation pattern across subcellular fractions in human post-mortem AD brain compared to age-matched controls (Chaparral AD proteomics). The mean log2 fold-change is −0.46, suggesting a modest overall decrease; however, the directionality varies depending on the subcellular compartment examined (mean log2FC: −0.4589, total fractions: 2, TMT-labeled proteomics across P2, P3, S2, and S3 fractions). This compartment-specific variation indicates that OTUB1 dysregulation in AD may involve differential localization or activity changes rather than uniform change across all cellular regions.