Translating Basic Research Into Clinical PracticeCHEST The Ubiquitin Proteasome System

Protein turnover plays an important role in a broad spectrum of cellular processes. Notably, approxi-mately 3 % to 5 % of our cellular proteins are degraded and resynthesized daily. 1 Until the mid-1970s it was widely believed that all intracellular proteins were degraded at the same rate in lysosomes in a nonspe-cifi c manner, despite the fact that proteins have a wide range of half-lives. 1 The existence of a novel, highly regulated, and specifi c degradation pathway was fi rst proposed by Ciechanover and colleagues 2 and Hershko and colleagues, 3 which was in agree-ment with the discovery of an ATP-dependent pro-teolytic system in reticulocytes that lack lysosomes. 4 As it was described 2 years later, this novel degrada-tion pathway was mediated by a small protein of 76 amino acid residues, termed ATP-dependent pro-teolysis factor-1 or ubiquitin. 5, 6 The Ubiquitin Enzymatic Cascade During ubiquitination, target proteins become “marked ” as ubiquitin covalently conjugates via its C-terminal glycine to protein substrates at the ́ -amino group of their lysine residues. 7 Conjugation of ubiq-uitin to a target protein occurs via an enzymatic cascade. 1, 7 Ubiquitin is fi rst activated by an ATP-dependent E1 ubiquitin-activating enzyme by the formation of a thiolester bond between the E1 enzyme and ubiquitin. Ubiquitin is then transferred via a transthiolation Ubiquitination and Proteolysis in Acut