A Novel Regulatory Mechanism to Regulate the Deubiquitinating Activity of USP25 by Oligomerization

151 Protein ubiquitination is a major post-translational mechanism that regulates fate and function of many proteins in the cell, either by regulating their abundance by the 26S-proteasome-ubiquitin system or by modulating protein activity by the attachment of the ubiquitin modifier [1]. Thus, in addition to targeting proteins for proteasomal degradation, ubiquitin plays a role in many other non-degradative processes in the cell, including transcription, cell cycle, DNA repair, apoptosis, immune response, endosomal sorting, among others [2]. Protein ubiquitination requires the coordination of an enzymatic cascade composed by the E1 activation enzyme, E2 conjugating enzyme, and the E3 ligase. Sometimes, E2 can directly guide ubiquitin to bind to the substrate, but in most circumstances, the cooperative work of E3 ligase is required for catalysis and specificity [3]. Deubiquitinating enzymes (DUBs) can reverse ubiquitination by removing ubiquitin from protein targets having an opposite function to the E3 ligases. Coordination of these two activities contributes to the fine-tune regulation of target ubiquitination inside the cell, and in some cases their abundance or half-life when ubiquitin targets protein degradation by the proteasome. Deregulation of DUBs activity can be linked to several diseases, such as cancer or neurodegeneration among others, indicating the major role of this proteolytic activity for a correct cellular homeostasis.