20S proteasome chymotrypsin-like subunits (PSMB5/PSMB8)

The 20S proteasome chymotrypsin-like subunits, primarily comprising the constitutive PSMB5 (beta-5) and the inducible PSMB8 (beta-5i/LMP7) proteins, are the principal catalytic components of the eukaryotic proteasome [2, 10]. These subunits function as threonine proteases that specifically cleave peptide bonds following large hydrophobic amino acid residues, representing the rate-limiting step in the degradation of intracellular proteins [1, 15]. In cancer cells, particularly in plasma cell dyscrasias like multiple myeloma, these subunits are essential for managing the high burden of misfolded proteins and maintaining cellular homeostasis [3, 17]. Therapeutic targeting of these subunits with proteasome inhibitors such as bortezomib and carfilzomib disrupts protein turnover, leading to the accumulation of pro-apoptotic factors and the induction of the unfolded protein response [5, 16]. While highly effective in treating hematologic malignancies, these therapies are associated with dose-limiting toxicities, including peripheral neuropathy and hematologic suppression [1, 15]. Furthermore, the emergence of resistance through mutations in the PSMB5 binding pocket remains a significant clinical challenge [13, 15].

Other names

Beta-5 subunitBeta-5i subunitLMP7MB1Chymotrypsin-like catalytic sitePSMB5PSMB8Proteasome subunit beta type-5Proteasome subunit beta type-8

Inhibition of the chymotrypsin-like proteolytic activity of the 20S proteasome core, leading to the accumulation of polyubiquitinated proteins, induction of endoplasmic reticulum stress, and subsequent apoptosis [3, 15, 16].