Home > Role of the Proteasome
The proteasome is an important regulator of normal cell function41,42
The ubiquitin proteasome pathway represents the major pathway for intracellular protein
degradation.41 More than 80% of cellular proteins are degraded through
this pathway, including those involved in processes such as cell cycle progression, apoptosis, DNA
repair, and protein quality control.43
The ubiquitin proteasome pathway41,42,44,45
Polyubiquitin chains target the protein for degradation by the 26S proteasome.
Ubiquitin molecules are removed and the protein is unfolded and fed into the inner 20S catalytic
chamber, where the protein is cleaved into small peptides using 3 main catalytic activities:
chymotrypsin-like (CT-L), trypsin-like (T-L), and caspase-like (C-L).45
Myeloma cells have increased dependence on proteasome function
Due to excess production of immunoglobulins and high rates of protein synthesis, myeloma cells have
increased demand for protein turnover.41,43 A stress response pathway called the unfolded protein
response (UPR) ensures that plasma cells can handle the proper folding of proteins and prevents the
accumulation of misfolded proteins. In myeloma cells, the burden on the UPR pathway is increased,
thereby increasing the need for degradation of rapidly accumulating misfolded proteins by the
proteasome.43
The proteasome also activates nuclear factor kappa B (NF-kB) signaling, which upregulates antiapoptotic
factors, cell adhesion molecules, cytokines, and growth factors that promote survival of myeloma
cells.21,42,43