Figure 1: The ubiquitin signaling system. Ubiquitin is activated by an ubiquitin-activating enzyme (E1), transferred to a ubiquitin-conjugating enzyme (E2) and, with the help of an ubiquitin ligase (E3), is covalently attached to lysine residues on specific substrates [2]. In addition to altering protein function or subcellular localization, monoubiquitination can target proteins for endocytosis and degradation in the multivesicular body (MVB)/lysosome pathway. Ubiquitin can form polyubiquitin chains via seven different lysine residues. Recent studies indicate that K63 chains are required to target substrates for degradation in the MVB/lysosome pathway [21]. Polyubiquitin chains using K48 linkages consisting of four or more ubiquitin molecules target proteins for degradation in the 26S proteasome. Recent studies indicate that polyubiquitin chains using other linkages like K11, K27, and K29 can also target proteins for proteasomal degradation [9, 10, 22]. DUBs function at multiple steps in the ubiquitin system: (1) DUBs are required to generate free Ub monomers from ubiquitin precursors, (2) DUBs counter the action of ubiquitin ligases, (3) DUBs function at the proteasome to edit ubiquitin chains, to remove ubiquitin prior to substrate degradation in the proteasome, and to recycle monomeric ubiquitin, and (4) DUBs function at the MVB to promote recycling of monomeric ubiquitin by removing ubiquitin prior to internalization of substrates into the MVB [15, 23, 24].