The ubiquitin-proteasome system (UPS) involves in polyubiquitination of the target protein prior to its degradation by the 26S proteasome. Polyubiquitination involves the combined action of three different enzymes: E1 (ubiquitin-activating), E2 (ubiquitin-conjugating), and E3 (ubiquitin ligase). The eukaryotic 26S proteasome is a large, multicatalytic protein complex composed of the 19S regulatory complex and the 20S core. The damaged, misfolded, or mutant proteins are degraded by three major proteolytic activities. Figure adapted from [62].