Alfred Lewis Goldberg (September 3, 1942 – April 18, 2023) was an American cell biologist-biochemist and professor at Harvard University. His major discoveries have concerned the mechanisms and physiological importance of protein degradation in cells. Of wide impact have been his lab's demonstration that all cells contain a pathway for selectively eliminating misfolded proteins, his discoveries about the role of proteasomes in this process and of the enzyme systems catalyzing protein breakdown in bacteria, his elucidating the mechanisms for muscle atrophy and the role of proteasomes in antigen presentation to the immune system, and his introduction of proteasome inhibitors now widely used as research tools and in the treatment of blood cancers.
 Goldberg was born in Providence, Rhode Island, on September 3, 1942. He graduated from Harvard College in 1963 magna cum laude in Biochemical Sciences (where he did his honor’s research in the laboratory of James Watson). He then spent a year as a Churchill Scholar at Cambridge University, where he studied physiology, before becoming a medical student at Harvard. After two years, he transferred to the Harvard Graduate School and in 1968 received his PhD in Physiology for studies in the laboratory of HM Goodman. He then joined the faculty at Harvard Medical School and rose to become full Professor of Physiology in 1977 and since 1993 Professor of Cell Biology. He also held visiting professorships at University of California (Berkeley) (1976), Institut Pasteur (Paris) (1995), and St John's College, Cambridge (2012).
 In the 1960s, when Goldberg began his research career, there was extremely 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, and his early studies in E. coli and reticulocytes first demonstrated that cells rapidly degrade misfolded proteins as arise through mutations and errors in protein synthesis. 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, they showed that the proteasome is the major site for protein breakdown in normal cells, is critical in activation of inflammatory responses, 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. Over 600,000 patients have now been treated with proteasome inhibits, which have extended their life spans and improved their quality of life.
 Another area where the Goldberg lab has made major contributions concerns the cellular mechanisms of muscle atrophy. His lab first identified factors that suppress muscle protein degradation (e.g., insulin) 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.
 From 1970, Goldberg was married to Joan Helpern Goldberg, a physician (hematologist). They had two children, Aaron Goldberg, a well-known jazz pianist, and Julie B. Goldberg, a software engineer.
 Alfred L. Goldberg died on April 18, 2023, at the age of 80.