Phosphorylation-dependent activity of the deubiquitinase DUBA

Abstract

Addition and removal of ubiquitin or ubiquitin chains to and from proteins is a tightly regulated process that contributes to cellular signaling and protein stability. Here we show that phosphorylation of the human deubiquitinase DUBA (OTUD5) at a single residue, Ser177, is both necessary and sufficient to activate the enzyme. The crystal structure of the ubiquitin aldehyde adduct of active DUBA reveals a marked cooperation between phosphorylation and substrate binding. An intricate web of interactions involving the phosphate and the C-terminal tail of ubiquitin cause DUBA to fold around its substrate, revealing why phosphorylation is essential for deubiquitinase activity. Phosphoactivation of DUBA represents an unprecedented mode of protease regulation and a clear link between two major cellular signal transduction systems: phosphorylation and ubiquitin modification.

Deubiquitylases From Genes to Organism

“…In a most direct case, the enzymatic activity of OTUD5 (DUBA) is entirely contingent on phosphorylation at a single serine residue, which interacts directly with the COOH-terminal tail of ubiquitin (97). Differential phosphorylation of USP8 at S680 and dephosphorylation of USP37 during M-phase of the cell cycle correspond with enhanced and reduced activity, respectively (100,176,190).…”

Usp9X Is Required for Lymphocyte Activation and Homeostasis through Its Control of ZAP70 Ubiquitination and PKCβ Kinase Activity

“…The (78). The observation that Usp9X catalytic activity is enhanced by phosphorylation of serine 1600 contributes to the emergent paradigm that DUBs can be regulated by cofactors, as is the case for USP1 (79), or by phosphorylation, which is the case for DUBA (80). It is perhaps not surprising that Usp9X is regulated in this manner given the importance of posttranslational modifications for the rapid temporal response required during T cell priming.…”

The p90 ribosomal S6 kinase–UBR5 pathway controls Toll-like receptor signaling via miRNA-induced translational inhibition of tumor necrosis factor receptor–associated factor 3

“…Upon the activation of TLR, DUBA is subsequently activated (35) and negatively regulates the induction of type I Interferon by removing the K63-linked ubiquitin chain of TRAF3 (20). DUBA stability is regulated by E3 ubiquitin ligase UBR5 (19) as well as its deubiquitinase activity (35). The question that UBR5 regulates the TLR-mediated TRAF3 signaling via DUBA was raised.…”