| OTUB1 is an OTU family deubiquitinase that regulates protein ubiquitination both by directly cleaving ubiquitin chains and by non‑catalytically blocking ubiquitin transfer, giving it a central role in tuning protein stability and signaling outputs downstream of multiple receptors. The protein contains an OTU catalytic domain with a conserved cysteine–histidine active site that can hydrolyze K48‑ and K63‑linked ubiquitin chains, and flanking N‑ and C‑terminal regions that engage E2 enzymes and ubiquitin‑loaded complexes, allowing OTUB1 to sense ubiquitin linkage type and interaction partners before deciding between catalytic and non‑catalytic modes of action. OTUB1 docks onto ubiquitin‑charged E2 conjugating enzymes such as UBE2N/UBE2D through defined interfaces and, when engaged with a proximal ubiquitin, can allosterically inhibit further ubiquitin transfer without necessarily promoting chain cleavage, so OTUB1 can stabilize substrates by shutting down E2 activity at specific signaling nodes. This non‑canonical inhibition is prominent in pathways controlled by c‑IAP1 and TNF receptor signaling, where OTUB1 limits K63‑ and linear ubiquitination events that would otherwise promote recruitment of TAK1, IKK complexes, and downstream NF‑κB activation, thereby restraining inflammatory and survival signaling and tuning the balance between pro‑ and anti‑apoptotic outputs. OTUB1 also deubiquitinates or protects regulators of the DNA damage response, including factors in the ubiquitin‑dependent ATM/ATR networks, positioning it as a modulator of checkpoint control, repair complex assembly, and recovery from genotoxic stress. OTUB1 as a frequently upregulated deubiquitinase that stabilizes oncogenic or pro‑survival substrates by preventing their proteasomal degradation, supports epithelial–mesenchymal transition and migration through regulation of EMT‑linked transcription factors and cytoskeletal regulators, and contributes to drug resistance by maintaining levels of checkpoint and immune‑evasive proteins such as PD‑L1 in specific tumor contexts. OTUB1 also has amyloidogenic properties and can form ordered aggregates, and its involvement in maintaining proteostasis via control of ubiquitin turnover connects it to pathways that determine neuronal vulnerability to misfolded proteins and stress. |
