The discovery of ubiquitin-dependent proteolysis

Abstract

In early 1980, Irwin A. Rose, Avram Hershko, and Aaron Ciechanover published two papers in PNAS that reported the astounding observation that energy-dependent intracellular proteolysis was far more complicated than the previously accepted models of lysosomal proteolysis or the action of ATP-dependent proteases such as bacterial lon. In fact, it has turned out to be even more complicated than they could have suspected. The general model of covalently attaching a small protein as a targeting signal has proved to be every bit as important to eukaryotic cells as the better understood modifications such as phosphorylation or acetylation. The key player in this modification, a small protein called ubiquitin (APF-1 in these papers), is the founding member of a large family of proteins containing the ␤-grasp fold and is used as a posttranslational targeting signal to modify the structure, function, and͞or localization of other proteins. The story of this discovery is a textbook example of the confluence of intellectual curiosity, unselfish collaboration, chance, luck, and preparation. It is a truism in science that the first example of any biological phenomenon is the hardest to prove. We rely so much on precedent to formulate our hypothesis that something truly unique and novel is often overlooked for many years. The covalent modification of proteins by the attachment of other proteins is one such example (1-6). As we now know, this modification is a targeting mechanism used to move proteins around in the cell. The ubiquitin family of modifiers (ubiquitin, Nedd8, SUMO, ISG15, etc.) has been implicated in the regulation of proteolysis, nuclear localization, chromatin structure, genetic integrity, protein quality control, and signaling (6). The prototypical example of this modification is the covalent attachment of ubiquitin to proteins to target them for degradation by the proteasome and was first reported in two PNAS papers published early in 1980 by the 2004 Nobel laureates in chemistry, Avram Hershko, Aaron Ciechanover, and Irwin A. Rose (Fig. 1), and their collaborators (1, 7). These two papers outlined the essentials of the system and were amazingly prescient in their interpretations and predictions based on simple biochemical analysis.The authors set out to explain a simple biological curiosity: the fact that intracellular proteolysis in mammalian cells requires energy. Melvin Simpson first showed this in his 1953 studies with isotopic labeling of cellular proteins (8), and for the next 25 years there were few insights into the mechanisms or metabolic logic of this observation. The hydrolysis of the peptide bond is exergonic, and there is no thermodynamic reason to use energy. The apparent requirement for energy could mean only that there was something we didn't understand. Part of the answer began to become apparent in the mid 1970s when Goldberg's group showed that damaged or abnormal proteins were rapidly cleared from the cell (9-11). He and Schimke (11) pointed out that enzymes that catalyzed rate-limiting ste...

Using the Ubiquitin-modified Proteome to Monitor Distinct and Spatially Restricted Protein Homeostasis Dysfunction

“…Protein ubiquitylation has been extensively studied for decades and the enzymatic machinery that participates in ubiquitylation has been amazingly well-characterized both functionally and structurally (35,36,54). Despite this extensive knowledgebase, the details regarding the function of individual ubiquitylation events for specific substrates are restricted to a small subset of highly regulated targets.…”

The Ubiquitination Machinery of the Ubiquitin System

“…The first studies leading to the 2004 Nobel Prize in Chemistry awarded for work on the ubiquitin system to researchers Avram Hershko, Aaron Ciechanover and Irwin Rose were published in 1978Rose were published in -1980 [for summary of this early work, see (Wilkinson, 2005)]. They were investigating in vitro proteolysis using lysates of rabbit immature red blood cells (called reticulocytes).…”

Non-canonical ubiquitin-based signals for proteasomal degradation

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Commentary 539Introduction Ubiquitylation [also known as ubiquitination, as coined by the discoverers of this modification with regard to its connection to proteolysis (Wilkinson, 2005)] is a three-step enzymatic reaction that is carried out by several enzymes: the ubiquitin-activating enzyme (E1), a ubiquitin carrier protein (E2; also known as ubiquitin-conjugating enzyme, UBC) and a ubiquitin-protein ligase (E3). An additional component of the ubiquitylation machinery has been described.

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