OTU domain-containing ubiquitin aldehyde-binding protein 1 (OTUB1)

OTU domain-containing ubiquitin aldehyde-binding protein 1 (OTUB1) is a cysteine protease deubiquitinase and the founding member of the OTU (ovarian tumor) family of DUBs, characterized by a catalytic OTU domain [3][1]. OTUB1 regulates protein homeostasis by specifically cleaving Lys48-linked polyubiquitin chains, thus stabilizing its protein substrates and antagonizing their proteasomal degradation [3][1]. Beyond this classical (canonical) DUB activity, OTUB1 employs a non-canonical mechanism where it binds to ubiquitin-charged E2-conjugating enzymes and blocks further ubiquitin transfer, inhibiting ubiquitination independently of its protease activity [1][3]. OTUB1 plays crucial roles in DNA damage response, immune regulation, and major cancer-associated signaling pathways (e.g., MAPK, ERα, mTORC1, p53) and contributes to tumor cell survival, proliferation, and therapy resistance [3][1]. OTUB1 is highly expressed in several tissues—in particular, brain, kidney, spleen, prostate, and liver—and knockout is embryonically lethal in mice [1][3]. Due to its central role in cancer and cellular homeostasis, OTUB1 has emerged as a potential therapeutic target, but no clinically approved drugs exist as of now; safety and specificity remain key challenges due to its essential cellular functions [1][3].

Other names

Ubiquitin thioesterase OTUB1Otubain-1Ubiquitin-specific-processing protease OTUB1OTB1OTU1HSPC263hOTU1FLJ20113FLJ40710Deubiquitinating enzyme OTUB1

Inhibition of OTUB1’s enzymatic (deubiquitinase) activity (potential small-molecule DUB inhibitors). Interference with OTUB1’s non-canonical E2 interaction to block ubiquitin conjugation [3][1].