Destructive Cleavage of Antigenic Peptides Either by the Immunoproteasome or by the Standard Proteasome Results in Differential Antigen Presentation

Abstract

The immunoproteasome (IP) is usually viewed as favoring the production of antigenic peptides presented by MHC class I molecules, mainly because of its higher cleavage activity after hydrophobic residues, referred to as the chymotrypsin-like activity. However, some peptides have been found to be better produced by the standard proteasome. The mechanism of this differential processing has not been described. By studying the processing of three tumor antigenic peptides of clinical interest, we demonstrate that their differential processing mainly results from differences in the efficiency of internal cleavages by the two proteasome types. Peptide gp100209–217 (ITDQVPSFV) and peptide tyrosinase369–377 (YMDGTMSQV) are destroyed by the IP, which cleaves after an internal hydrophobic residue. Conversely, peptide MAGE-C2336–344 (ALKDVEERV) is destroyed by the standard proteasome by internal cleavage after an acidic residue, in line with its higher postacidic activity. These results indicate that the IP may destroy some antigenic peptides due to its higher chymotrypsin-like activity, rather than favor their production. They also suggest that the sets of peptides produced by the two proteasome types differ more than expected. Considering that mature dendritic cells mainly contain IPs, our results have implications for the design of immunotherapy strategies.

Why the Structure but Not the Activity of the Immunoproteasome Subunit Low Molecular Mass Polypeptide 2 Rescues Antigen Presentation

“…Our results strongly suggest that the influenza matrix M1 58-66 epitope is destroyed by b5 and can be rescued by a b5 inhibitor and, thus, LMP7 induction protects the CTL epitope from destruction by b5. In line with our results are the data from Chapiro et al (43), which demonstrated that the MAGE-C2 336-344 peptide is produced by the immunoproteasome, but not by the constitutive proteasome, because the latter destroys the Ag by making an internal cleavage occurring after an acidic residue.…”

Long‐lasting cross‐presentation of tumor antigen in human DC

“…We conclude that the crosspresentation of the gp100 peptide is mostly independent of the proteasome. It has been described previously that these two epitopes are cleaved in vitro by purified immunoproteasome [42,43]. It is also known that both immature and mature DC contain immunoproteasomes.…”

“…Further dilutions were performed in PBS. The MelanA/MART-1 short (EAAGIGILTV) or long (KGHGHSYTTAEEAAGIGILTVILGVL) peptides [43] and the gp100 short (IMDQVPFSV) or long (AHSSSAF-TIMDQVPFSVSVSQLR) peptides [60] were used. An additional synthesis of the long MelanA peptide includes an N-terminal biotin.…”

Identification of an HLA‐A24‐restricted cytotoxic T lymphocyte epitope from human papillomavirus type‐16 E6: The combined effects of bortezomib and interferon‐γ on the presentation of a cryptic epitope

“…34 Second, IFN-g gave a marginal effect on E6 mRNA expression, but its favorable effect on increased cell surface expression of HLA class I molecules was evident in most cell lines tested, which is critical for efficient recognition by CD8 1 T cells. Nevertheless, it is likely that IFN-g treatment facilitated either active destruction of the E6 49-57 epitope or failure in epitope generation by immunoproteasome, 42 which is induced by IFN-g as observed in IFN-gtreated SiHa/E6-E7 cells. It remains to be determined in the future whether IFN-g secreted from tumor-reactive CTLs might unexpectedly allow tumor cells to escape by further reducing the amount of epitopes possessing kinetics similar to E6 [49][50][51][52][53][54][55][56][57] .…”