| Proteasome activator subunit 1 (PSME1, also termed PA28α) is an interferon-γ–inducible regulatory protein of the 11S proteasome activator complex that binds the ends of the 20S proteasome core and modulates peptide generation for MHC class I antigen presentation. PA28α assembles with the homologous PA28β subunit to form a hetero-oligomeric ring that caps the 20S core particle, opening the axial gate and altering proteasomal cleavage patterns toward production of peptides with termini suitable for loading onto MHC class I molecules, distinct from those generated by the constitutive 26S proteasome with 19S regulatory particles. Interferon-γ upregulates expression of PA28α/PSME1 in antigen-presenting cells and promotes incorporation of PA28 into immunoproteasomes that also contain inducible catalytic subunits such as PSMB8, PSMB9 and PSMB10, creating a specialized proteolytic complex optimized for generating antigenic epitopes from endogenous and exogenous proteins. PA28α–containing proteasomes enhance processing of selected viral epitopes; PA28 selectively increases presentation of defined viral MHC class I peptides, and downregulation of PA28 in tumor cells impairs presentation of tumor-associated antigens such as TRP2, indicating that PSME1-dependent activation of the 20S core directly influences the repertoire and efficiency of peptide presentation to cytotoxic T lymphocytes. In vivo disruption of the PA28β gene in mice results in loss of both PA28α and PA28β polypeptides and markedly inhibits immunoproteasome assembly, leading to altered processing of epitopes and impaired cytotoxic T-cell responses, which demonstrates that the PA28α/β complex is required for efficient antigen processing and normal adaptive immune function. Structural and biochemical analyses show that PA28α/β binds the proteasome α-ring via multiple contact sites, induces conformational changes that open the gate and promotes increased throughput of peptide products without requiring ubiquitin or ATP, linking PSME1 activity to ubiquitin-independent proteasomal degradation and fine-tuning of peptide length and sequence composition. Across cancers, expression of PSME1 and other immunoproteasome components correlates with immune cell infiltration and activation of anti-tumor immune pathways, and in non-small cell lung cancer and triple-negative breast cancer, high levels of immunoproteasome subunits and interferon-inducible regulators such as PA28β associate with increased MHC class I expression and tumor-infiltrating lymphocytes, while suppression of immunoproteasome activity contributes to immune evasion in metastatic lesions. PSME1 thus operates as a key regulatory subunit that links interferon-γ signaling and immunoproteasome assembly to the quality and quantity of peptides supplied to the MHC class I pathway, and its expression status provides insight into antigen processing capacity, T-cell responsiveness and the potential impact of proteasome-targeting therapies in immune-related diseases and cancer. |
