Poly-ubiquitylation of target proteins through linkage at K48, is now the most thoroughly studied of the various chain linkages, and was once considered the hallmark of this post-translational modification. It is now clear that many, if not all, poly-Ub chain topologies likely play distinct and important roles in regulating cellular processes. Nevertheless, K48 linkage remains a critical pathway for the cells to maintain homeostasis through proteolytic degradation, and as such remains very intriguing for the study of DUBs that play a role in the degradation, as well as the proteasome itself. These di-ubiquitin chains are generated from the enzymatic linkage (E2-25K) of wild-type ubiquitin through lysine 48. The most distal ubiquitin contain