Intracellular protein degradation has been studied for more than half a century, and it became clear early on that such degradation is highly selective, with individual protein half-lives ranging from minutes to years.

Most regulated protein degradation in eukaryotes is executed by the ubiquitin–proteasome system. A well-defined series of enzymes termed E1, E2, and E3 orchestrates the attachment of polyubiquitin to proteins.  This covalent modification of the substrate targets the conjugated protein to a multicatalytic protease complex, the 26S proteasome.