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A Lysine Residue at the C-Terminus of MHC Class I Ligands Correlates with Low C-Terminal Proteasomal Cleavage Probability

ORCID
0000-0003-2462-2675
Affiliation
Chair of Physiology, Department of Veterinary Sciences, LMU Munich, Martinsried, 82152 Planegg, Germany
Schmalen, Adrian;
Affiliation
Comprehensive Pneumology Center (CPC), University Hospital, Ludwig-Maximilians-University, Helmholtz Center Munich, Member of the German Center for Lung Research (DZL), 81377 Munich, Germany
Kammerl, Ilona E.;
ORCID
0000-0003-3678-7995
Affiliation
Research Center Borstel, Leibniz Lung Center, Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL), 23845 Borstel, Germany
Meiners, Silke;
ORCID
0000-0003-4709-9266
Affiliation
Immunoanalytics Research Group—Tissue Control of Immunocytes, Helmholtz Center Munich, 81377 Munich, Germany
Noessner, Elfriede;
ORCID
0000-0003-0375-3190
Affiliation
Chair of Physiology, Department of Veterinary Sciences, LMU Munich, Martinsried, 82152 Planegg, Germany
Deeg, Cornelia A.;
ORCID
0000-0002-1630-6827
Affiliation
Core Facility—Metabolomics and Proteomics Core, Helmholtz Center Munich, German Research Center for Environmental Health (GmbH), 80939 Munich, Germany
Hauck, Stefanie M.

The majority of peptides presented by MHC class I result from proteasomal protein turnover. The specialized immunoproteasome, which is induced during inflammation, plays a major role in antigenic peptide generation. However, other cellular proteases can, either alone or together with the proteasome, contribute peptides to MHC class I loading non-canonically. We used an immunopeptidomics workflow combined with prediction software for proteasomal cleavage probabilities to analyze how inflammatory conditions affect the proteasomal processing of immune epitopes presented by A549 cells. The treatment of A549 cells with IFNγ enhanced the proteasomal cleavage probability of MHC class I ligands for both the constitutive proteasome and the immunoproteasome. Furthermore, IFNγ alters the contribution of the different HLA allotypes to the immunopeptidome. When we calculated the HLA allotype-specific proteasomal cleavage probabilities for MHC class I ligands, the peptides presented by HLA-A*30:01 showed characteristics hinting at a reduced C-terminal proteasomal cleavage probability independently of the type of proteasome. This was confirmed by HLA-A*30:01 ligands from the immune epitope database, which also showed this effect. Furthermore, two additional HLA allotypes, namely, HLA-A*03:01 and HLA-A*11:01, presented peptides with a markedly reduced C-terminal proteasomal cleavage probability. The peptides eluted from all three HLA allotypes shared a peptide binding motif with a C-terminal lysine residue, suggesting that this lysine residue impairs proteasome-dependent HLA ligand production and might, in turn, favor peptide generation by other cellular proteases.

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