Irwin Rose, one of the biochemists who shared the 2004 Nobel Prize in Chemistry (link is external) for the discovery of ubiquitin-mediated protein degradation, died last month at the age of 88.
Rose first became interested in the protein disposal system of the cell in the 1950’s. At a time when the main focus of biochemical research was on the methods of molecular synthesis, his interest lay in the exact opposite.
In 1975 a protein was discovered that appeared to be present in all tissues and cells, though its function remained a mystery. Named ubiquitin, in the late 1970’s Rose collaborated with Avram Hershko and Aaron Ciechanover from the Technion Institute of Technology in Israel to pursue the answers to the role of this protein. At this time Rose was based at the Fox Chase Cancer Centre in Philadelphia, where he spent the majority of his career, and his collaborators came to the US for a year to work with him on the regulation of the breakdown of cellular protein by ubiquitin.
Their experiments showed that ubiquitin serves as a molecular marker that when attached to a protein indicates its requirement for degradation via the proteasome. Knowledge of the ubiquitin proteasome system has helped researchers to understand diseases like cystic fibrosis, Parkinson’s and many types of cancer, that arise when the system does not function correctly. The teams research also lead directly to the development of Velcade, a treatment for multiple myeloma, which was licensed for use in the US in 2003.
Further research into the function of ubiquitin within the cell has uncovered multiple roles for this protein tag. Ubiquitin can be attached to proteins either a monomer or as a polyubiquitin chain linked via one of the seven lysine residues within the sequence or via the N-terminal methionine reside. Depending upon which residue is used to link ubiquitin with its target protein a variety of branching patterns can be generated in the polyubiquitin chains. This versatility in the system is highly regulated and increases the possible signalling functions of these post-translational modifications.
K48-linked polyubiquitin chains are associated with protein degradation via the proteasome, as Rose and his collaborators studied. K63-linked chains function within DNA-damage responses. Yet the roles of the other lysine-linked ubiquitin chains in intracellular signalling are not fully defined. K6-linked polyubiquitin chains may be involved in DNA repair, while K33-linked chains have been associated with post-Golgi transport and T-cell receptor signalling.
In the three decades since the discovery of the ubiquitin proteasome system research has been held back due to the fact that only two antibodies have been generated to these important ubiquitin chains. A crucial need in this research field has been met by the launch of Affimer technology, targeting not only ubiquitin and K48-linked chains, but also K6- and K33-linked polyubiquitin, to which there is no antibody equivalent available. This opens the door to new research possibilities and raises the potential for the development of new therapies based on targets within the ubiquitin signalling pathways.
After his retirement from the Fox Chase Centre in Philadelphia he moved to California, where his incessant interest in biochemistry drove him to search out lab space at the University of California, Irvine, where he was soon appointed to a research position. Apparently, even the announcement of his Nobel Prize win didn’t deter him from his research and after dealing with the press calls he was back in the lab by the end of the day.