Deubiquitination Reactions on the Proteasome for Proteasome Versatility

Abstract

The 26S proteasome, a master player in proteolysis, is the most complex and meticulously contextured protease in eukaryotic cells. While capable of hosting thousands of discrete substrates due to the selective recognition of ubiquitin tags, this protease complex is also dynamically checked through diverse regulatory mechanisms. The proteasome’s versatility ensures precise control over active proteolysis, yet prevents runaway or futile degradation of many essential cellular proteins. Among the multi-layered processes regulating the proteasome’s proteolysis, deubiquitination reactions are prominent because they not only recycle ubiquitins, but also impose a critical checkpoint for substrate degradation on the proteasome. Of note, three distinct classes of deubiquitinating enzymes—USP14, RPN11, and UCH37—are associated with the 19S subunits of the human proteasome. Recent biochemical and structural studies suggest that these enzymes exert dynamic influence over proteasome output with limited redundancy, and at times act in opposition. Such distinct activities occur spatially on the proteasome, temporally through substrate processing, and differentially for ubiquitin topology. Therefore, deubiquitinating enzymes on the proteasome may fine-tune the degradation depending on various cellular contexts and for dynamic proteolysis outcomes. Given that the proteasome is among the most important drug targets, the biology of proteasome-associated deubiquitination should be further elucidated for its potential targeting in human diseases.

Beyond K48 and K63: non-canonical protein ubiquitination

“…In the process of protein degradation, deubiquitinases (DUBs) mediate the detachment of Ub chains from the protein to recycle Ub monomers for the next round of ubiquitination. Beyond their recycling role, DUBs are now widely recognized to coordinate proteasomal processing steps and modulate substrate degradation, imposing a checkpoint for proteasomal processing (recently reviewed in [ 7 ]).…”

Molecular Mechanisms of DUBs Regulation in Signaling and Disease

“…The JAMMs is the only family of deubiquitinating enzymes belonging to the metalloprotease family, which contain a Zn atom in the active site. Members of this family are occasionally subunits of large protein complexes, such as COP9 signalosome complex (CSN5 and CSN6 subunits), the 26S-proteasome (PSMD14/Rpn11 and PSMD7/Rpn8 subunits), and the Eukaryotic translation initiation factor 3 (EIF3) (EIF3H and EIF3F subunits) [70][71][72][73][74][75][76]. In this family, AMSH, AMSH-LP, and BRCC36 have been shown to have specificity for K63-linked ubiquitin chains [77,78], and CNS5/COPS5 has activity against NEDD8, another type of ubiquitin-like modifier [79].…”

Role of Proteasomes in Inflammation

“…One prime example of such regulators is the 19S RP [ 32 ], a complex of approximately 20 subunits which is essential for the recognition of K48-linked polyubiquitinated proteins via the Rpn10 and Rpn13 subunits [ 33 , 34 ]. The 19S RP also ensures the ATP-dependent unfolding of substrates as well as the removal of the ubiquitin moieties before translocation into the 20S CP [ 35 , 36 , 37 ]. Other regulators include the proteasome activators (PA) 28-αβ, PA28-γ and PA200 [ 27 ].…”