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Schmalen, A. ; Kammerl, I.E. ; Meiners, S.* ; Nößner, E. ; Deeg , C.A.* ; Hauck, S.M.

A lysine residue at the C-terminus of MHC class I ligands correlates with low C-terminal proteasomal cleavage probability.

Biomolecules 13:18 (2023)

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	Open Access Gold

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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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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Hla-a*03:01 ; Hla-a*11:01 ; Hla-a*30:01 ; Immunopeptidomics ; Non-canonical Mhc Class I Ligands ; Peptide Origin ; Peptide Processing ; Proteasomal Cleavage Probability ; Proteasome Independent; Peptide; Antigen; Binding; Identification; Degradation; Specificity; Generation; Inhibitors; Molecules; Alignment

ISSN (print) / ISBN 2218-273X

e-ISSN 2218-273X

Journal Biomolecules

Quellenangaben Volume: 13, Issue: 9, Article Number: 18

Publisher MDPI

Publishing Place Basel

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) CF Metabolomics & Proteomics (CF-MPC)
Institute of Lung Biology (LHI)
CF Immunoanalytics (IMA)

Grants Deutsche Forschungsgemeinschaft in the SPP 2127