Alfred L. Goldberg

Alfred L. Goldberg

Professor of Cell Biology
Alfred L. Goldberg

Our laboratory is studying the regulation, mechanisms, and physiological importance of protein breakdown in animal cells. We are presently attempting to understand how the 26S proteasome degrades ubiquitin-conjugated proteins, how it unfolds globular proteins and translocates them into the 20S proteasome for degradation, how peptide products exit these particles, and the subsequent fates of these peptides in cells. We are now particularly interested in the molecular mechanism by which the regulatory ATPases open a gated channel to enable substrate proteins to enter the 20S and be degraded. Knowledge gained in our lab about proteasome function has led to the development of proteasome inhibitors that have had wide applications as scientific tools and in the therapy of certain cancers (e.g. multiple myeloma). We believe that further insights into proteasome function should allow the development of more selective therapeutic agents, including ones that target the proteasomes of pathogenic organisms (e.g. tuberculosis).

In skeletal muscle, protein breakdown rises upon disuse, fasting and in most systemic diseases (e.g. cancer, sepsis, cardiac failure, diabetes) and causes muscle atrophy. This debilitating loss of muscle mass is due to excessive protein breakdown by the ubiquitin-proteasome pathway. A major goal of our research is to elucidate its biochemical basis. We have discovered a number of atrophy-specific genes (“atrogenes”), including a muscle-specific ubiquitin ligase (E3), atrogin-1, which is dramatically induced during atrophy. We have recently identified the hormone (e.g. insulin) signaling pathway (PI3K/Akt), and transcription factors (Foxo) that regulate atrogin-1 expression and muscle atrophy. We are trying to elucidate their specific roles in preventing or initiating the atrophy process in order to develop rational therapies for this condition.

Another important function of intracellular proteolysis is to selectively eliminate proteins with abnormal structures as may arise by mutation or postsynthetic damage by free radicals. Molecular chaperones are critical in targeting such misfolded proteins for rapid degradation. We are attempting to elucidate this new role of the chaperones, and to understand how the chaperone and the ubiquitin proteasome system collaborate to protect cell proteins against various stressful conditions and genetic and neurodegenerative diseases (e.g. Huntington's or Parkinson's diseases).

During the degradation of cell proteins, proteasomes also generate the peptides that are presented to the immune system on MHC-class I molecules. We are trying to clarify this role of the proteasome in antigen presentation, and to understand how interferon-g stimulates this process in disease states. Recently, we identified a key peptidase in the ER, ERAP1, which trims proteasome products to the correct size (8-9 residues) for binding to MHC-class I molecules. It thus plays a key role in host defenses against viruses and cancer.

Contact Information

Harvard Medical School
240 Longwood Avenue
Boston, MA 02115
p: 617-432-1855