| Proteasome 20S β6 (PSMB6) is a constitutive β-type subunit of the 20S core proteasome that contributes to the major ATP/ubiquitin-dependent proteolytic machinery responsible for degradation of most intracellular proteins and maintenance of protein homeostasis. Within the four-ring 20S core, PSMB6 resides in the β-ring and provides caspase-like or postacidic peptidylglutamyl-hydrolyzing activity, cleaving peptide bonds after acidic residues and shaping the overall spectrum of proteasome-generated peptides. Association of the 20S core containing PSMB6 with two 19S regulatory particles forms the 26S proteasome, which recognizes ubiquitinated substrates, unfolds them and translocates them into the catalytic chamber, where PSMB6 and other β subunits cooperate to remove misfolded or damaged proteins and proteins whose functions are no longer needed, thereby supporting processes such as cell-cycle progression, transcriptional regulation, and stress responses. Alternative association of the PSMB6-containing 20S core with PA28 or PA200 regulatory complexes enables ubiquitin-independent proteolysis, with 20S–PA28 complexes contributing to the generation of a subset of MHC class I–presented antigenic peptides and 20S–PA200 complexes supporting spermatogenesis, highlighting roles for PSMB6-containing cores in both general proteostasis and antigen-processing routes. In immune cells, interferon-γ and other proinflammatory cytokines induce expression of immunoproteasome catalytic subunits PSMB9, PSMB10 and PSMB8, which replace the constitutive β1, β2 and β5 subunits including PSMB6 in the 20S core to form immunoproteasomes; this remodeling reduces caspase-like activity and enhances chymotrypsin- and trypsin-like activities, creating C-terminal cleavage patterns that favor loading of peptides onto MHC class I molecules. At the functional level, PSMB6 acts as part of the standard proteasome in pathways such as COP1 autodegradation and CDK-mediated phosphorylation and removal of Cdc6, integrating proteasomal turnover with regulation of E3 ligases and replication licensing factors. Experimental inhibition or knockdown of PSMB6 in deltamethrin-resistant mosquito cells increases susceptibility to insecticide and decreases cell viability under treatment, demonstrating that PSMB6-containing proteasomes support stress adaptation and xenobiotic resistance in this model and that proteasome inhibitors such as bortezomib or MG‑132 can synergize with deltamethrin by targeting PSMB6-dependent proteolysis. Proteasome 20S β6 acts as a caspase-like catalytic subunit embedded in the constitutive 20S core that participates in ATP/ubiquitin-dependent and -independent proteolysis, is replaced by inducible β1i in immunoproteasomes during inflammatory responses, and contributes to pathways ranging from protein quality control and replication factor turnover to xenobiotic resistance and antigen peptide generation. |
