Drosophila Tak1 Mediates the Condensation and Deubiquitinase Activity of Otu in a Kinase-Independent Manner

In the intricate molecular world, post-translational modifications play pivotal roles in modulating protein activity and function. The Drosophila melanogaster genome encodes an array of enzymes to mediate these processes. Here, we elucidate a previously unrecognized connection between the Drosophila transforming growth factor-β-activated kinase 1 (dTak1) and the deubiquitinase Ovarian tumor (Otu). We demonstrate that dTak1 mediates both the phase-separated condensation and the deubiquitinase enzymatical activity of Otu in a manner independent of its kinase function. Using a combination of biochemical assays and in vivo genetic interactions, our findings highlight the significance of dTak1 in orchestrating the assembly of Otu condensates, and consequently, in the regulation of Otu’s biological functions. Our studies underscore the multifaceted nature of protein-protein interactions and open up avenues for exploring non-traditional roles of kinases in cellular processes.