Figure 1. Major pathways for ubiquitin-dependent protein degradation in eukaryotic cells.

Proteasome-mediated degradation of ubiquitinated proteins (a). Ubiquitination is a process whereby target proteins can be marked for degradation by the 26S proteasome. It is a multi-step enzymatic process, using three classes of enzymes (E1s, E2s, and E3s), and involves the sequential transfer of ubiquitin from these enzymes to a lysine residue on the target protein. Ubiquitin is first activated by the ubiquitin-activating enzyme (E1) in an ATP-dependent reaction in which the C terminal glycine residue of ubiquitin binds to the active-site cysteine of an E1 in a thioester linkage. The activated ubiquitin is passed to E2 ubiquitin-carrier enzymes and then to E3 ubiquitin ligases. De-ubiquitinating enzymes (DUBs) reverse the ubiquitination process. DUBs are cysteine proteases that generate free usable ubiquitin from a number of sources including ubiquitin-protein conjugates, ubiquitin-adducts, and ubiquitin precursors. Degradation of ubiquitinated membrane proteins by the lysosome (b). Ubiquitination, usually in the form of single (mono) or short-chain ubiquitin modifications (K63-linkages in many cases) can result in the endocytosis of membrane proteins. In early endosomes, non-ubiquitinated proteins can recycle back to the plasma membrane or be directed to other intracellular compartments. In contrast, ubiquitinated proteins are sorted into multivesicular bodies (MVB) and eventually targeted to the lysosome for degradation. Deubiquitination of cargos plays a critical role in the regulation of intracellular trafficking through the endosomal sorting complexes required for transport (ESCRT) pathway and in some cases ensures recycling of internalized cargos to the plasma membrane.