Avram Hershko (left) & Aaron Ciechanover

Last month, the 2000 Albert Lasker award for basic medical research was awarded to Avram Hershko and Aaron Ciechanover, of the Technion Israel Institute of Technology, and to Alexander Varshavsky, of the California Institute of Technology, for their pioneering work that led to the discovery of the ubiquitin pathway that is responsible for intracellular proteolysis.

Alexander Varshavsky

In the 1970s, Hershko and his student Ciechanover sought to identify the elusive energy-dependent proteolytic system, as distinct from lysosomal protein breakdown. The breakthrough occurred when they were able to develop a cell-free system for ATP-dependent protein degradation. Through classical purification and reconstitution strategies, they soon realized that they were not dealing with a single enzyme, but rather with a complex system composed of several biochemically distinct factors. The first of these to be identified was a protein that is now called ubiquitin (a previously known protein with no known function at the time), which becomes covalently linked to proteins that are targeted for degradation. In the early 1980s, they identified the complex enzymatic machinery behind this process and showed that it involves an ubiquitin-activating enzyme E1, an ubiquitin-carrier protein E2, and an ubiquitin–protein ligase E3. The actual proteolytic machinery that recognizes and degrades ubiquitin-tagged proteins, the 26S proteasome, was identified by Rechsteiner and colleagues in 1986.

Whereas the initial studies of the ubiquitin-dependent proteolysis system had been carried out using artificial substrates in vitro, Hershko and Ciechanover later developed antibodies against ubiquitin to provide the first evidence that cells use the ubiquitin system to degrade proteins. In the mid-1980s, members of Varshavsky's laboratory at MIT used yeast genetics to demonstrate conclusively that this system is indeed involved in the regulation of protein turnover in vivo. Varshavsky, his graduate student Dan Finley, and Ciechanover, who had joined another MIT laboratory as a postdoctoral fellow, found that a yeast mutant lacking an E1 enzyme was unable to degrade many short-lived proteins. As this mutant exhibited a cell-cycle-arrest phenotype, they speculated that ubiquitin-dependent proteolysis may be directly involved in regulation of the cell cycle, an idea that was later proved to be correct. Since then, the ubiquitin–proteasome pathway has not only been implicated in cell-cycle control but in most, if not all, cellular processes, including signal transduction, transcription, the response to DNA damage, quality control, and the generation of antigenic peptides. Moreover, altered proteasome function has been implicated in a variety of diseases, including neurodegeneration, cancer and viral infections.

The award of this year's Lasker prize to Hershko, Ciechanover and Varshavsky is excellent news for basic cell-biological research. It emphasizes once again the power of combining biochemical approaches and in vitro reconstitution systems with the advantages of genetic model systems. The award also comes at a time when the ubiquitin field is developing new ideas at an exciting pace. There are indications that at least some substrates can be targeted for proteasomal degradation independently of ubiquitin modification. Conversely, several ubiquitin-related molecules have been identified that can be covalently linked to proteins, for example to regulate their localization or to protect them from ubiquitination, rather than targeting them for degradation. Perhaps one of the most exciting developments derives from recent reports showing that ubiquitin modification may have functions other than targeting proteins for proteasomal degradation, such as the internalization of membrane proteins, partial proteolysis to liberate active transcription factors from inactive precursors, and possibly the regulation of protein–protein interactions. There is no doubt that the foundations laid by this year's Lasker awardees have fuelled exciting research in this important field, and will continue to do so.