Otubain deubiquitinases: Multi-layered regulators of cell fate, development, and stress responses across kingdoms

Otubain deubiquitinating enzymes are pivotal regulators of cell fate, development, and stress responses across animals, plants, and fungi. This review highlights their conserved and pleiotropic functions in orchestrating proteostasis, organogenesis, immune modulation, metabolic adaptation, and stress tolerance. Mechanistically, Otubains operate in both enzyme-dependent and -independent manner, modulating key processes including ubiquitin-proteasome-mediated degradation, DNA damage repair, autophagy, and cell death. Notably, Otubains are subject to multi-layered regulations, including epigenetic, transcriptional, post-transcriptional, and post-translational modifications, as well as RNA-mediated scaffolding. In plants, Otubain homologs control grain size and organ morphogenesis, while in fungi, they mediate stress responses and sexual development. These findings underscore the cross-kingdom conservation of Otubain function and reveal their potential as universal modulators. Furthermore, Otubains represent promising targets for therapeutic intervention, crop improvement, and pathogen management. This review synthesizes recent advances in Otubain biology, emphasizing integrative regulatory networks and translational potential, while highlighting key unresolved questions about their functional diversity.