The ubiquitin proteasome pathway represents the major pathway for intracellular
protein degradation.20 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.22
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).24
Due to excess production of immunoglobulins and high rates of protein synthesis, myeloma cells have increased demand for protein turnover.20,22 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.22
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.15,21,22
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