In the 1960s, when Goldberg began his research career, there was little interest in protein degradation. However, as a graduate student, Goldberg showed that the loss of
muscle mass upon
denervation or
fasting occurred primarily through acceleration of protein degradation. As an assistant professor, he decided to focus on this neglected area, These studies defined for the first time many of the key features of intracellular protein degradation, especially its role in protein quality control in eliminating aggregation-prone proteins and its requirement for metabolic energy (ATP). At that time, the lysosome was believed to be the only site for protein degradation in cells. However, in 1977, his lab demonstrated that the rapid breakdown of misfolded proteins in reticulocytes is catalyzed by a non-lysosomal, ATP-dependent system, now called the Ubiquitin Proteasome System. The seminal studies of
Hershko,
Ciechanover, and
Irwin Rose on these preparations uncovered the role of ubiquitination in marking such proteins for degradation. Simultaneously, Goldberg and coworkers discovered that protein degradation in
bacteria, which lack
ubiquitin, and
mitochondria involves a new type of
enzyme,
ATP hydrolyzing
protease complexes (
protease Lon/La, ClpAP, HslUV). They went on to describe their novel mechanisms and induction in stressful states. In 1987, his laboratory and Rechsteiner’s described the much larger
ATP-dependent
proteolytic complex that degrades ubiquitinated proteins in
reticulocytes. He named it the
26S proteasome to distinguish it from the smaller particle, which he named the
20S proteasome, and which they later showed comprises the proteolytic activity of the 26S complex. Their subsequent studies defined many of the proteasome’s novel biochemical features, especially its ATP-dependent mechanism, peptide products, and cellular functions. Their recent research has shown that cellular rates of degradation are controlled in part by regulation of
26S proteasome activity, including by
protein kinases. Of major scientific and medical impact was his lab’s development of
proteasome inhibitors that block degradation in cells. In collaboration with a small biotech company (Myogenics/Proscript), which he founded, they introduced in 1994 the inhibitor,
MG132, which has been used in many thousands of publications and has enabled major advances in knowledge about the importance of protein degradation. In introducing these
inhibitors, and is the source of most
antigen peptides presented on surface MHC Class 1 molecules, which is critical in immune defense against
viruses and
cancer. His long collaboration with Ken Rock further elucidated this process, identified the unique properties of the
proteasomes in immune tissues, and defined the roles of cellular peptidases (especially
ERAP1) in further processing proteasome products so they fit into MHC Class 1 molecules. Most importantly, Goldberg’s efforts initiated the development by the company of proteasome inhibitor
Bortezomib/
Velcade, which is used worldwide to treat the common
hematological cancer,
multiple myeloma. or enhance it (e.g., disuse,
cancer cachexia), and subsequently showed that various types of
muscle wasting occur through
transcription of a common set of atrophy-related genes (atrogenes). They also identified the critical
transcription factor triggering this atrophy program (FoxO3) and elucidated the mechanisms that disassemble the muscles’ contractile apparatus during atrophy. ==Personal life and death==