The ubiquitin (Ub)-dependent and Ub-independent proteasomal degradation is crucial for the turnover of damaged and regulatory proteins within cells. This mechanism also generates antigenic peptides that can be loaded on to class I major histocompatibility complex (MHC I) molecules and presented externally to cytotoxic CD8+ T lymphocytes (CTLs) (Mamrosh JL et al., 2023; reviewed by Embgenbroich M & Burgdorf S 2018; Admon A 2023).
This Reactome event shows Ub-independent antigen processing by immunoproteasome, a specialized form of the proteasome in which the standard catalytic subunits PSMB6 (β1), PSMB7 (β2), and PSMB5 (β5) of 20S core particle (CP) are replaced with PSMB9 (β1i), PSMB10 (β2i), and PSMB8 (β5i), respectively (Shin EC et al., 2006; Bai M et al., 2014; Santos R et al., 2017). This variation of the core particle is known as 20S iCP. Immunoproteasomes utilize the PA28 regulatory particle, a heteroheptamer of 4xPSME1:3xPSME2, to degrade substrates (Lesne J et al., 2020; Chen J et al., 2021). The catalytic and regulatory subunits of immunoproteasomes are constitutively expressed in various immune cells, such as T cells, B cells, and antigen-presenting cells (Inholz K et al., 2024; reviewed by McCarthy MK & Weinberg JB 2015). Their expression is also induced by pro-inflammatory cytokines such as interferon-gamma (IFNγ), type I interferons, and tumor necrosis factor alpha (TNF-α) in infected cells (Heink S et al. 2005; Niewerth D et al., 2014; reviewed by Kimura H et al. 2015; McCarthy MK & Weinberg JB 2015). While both standard catalytic β subunits of 20S CP and their immunoproteasome counterparts of 20S iCP exhibit caspase-like, trypsin-like, and chymotrypsin-like proteolytic activities, immunoproteasomes possess enhanced chymotrypsin- and trypsin-like activities, alongside with the reduced caspase-like activity (Cascio P et al., 2001; Kim S et al., 2022). These distinct enzymatic properties of immunoproteasomes generate C-terminal cleavage patterns that enhance loading of peptides onto MHC class I for immune presentation to killer T cells (reviewed in Tomko and Hochstrasser 2013). The peptides generated by the proteasome are either of the ideal length for binding to MHC class I molecules, ranging from 8 to 9 amino acids, or can be further cleaved by cytoplasmic aminopeptidases, including leucine aminopeptidase, puromycin-sensitive aminopeptidase, bleomycin hydrolase, and tripeptidyl peptidase II (Hearn A et al., 2010; Kim E et al., 2010). Within the endoplasmic reticulum (ER), extended peptides can be further trimmed by ER-resident aminopeptidases (ERAP1 and ERAP2) before being loaded onto MHC class I molecules (Rock KL et al., 2004; Saveanu L et al., 2005; Hearn A et al., 2010).
