HLA class I anchor motifs contribute to antigen presentation from non-canonical open reading frames
- 1Presentation and Immune Regulation Unit, Centro Nacional de Microbiología, Instituto de Salud Carlos III
Abstract
Non-canonical open reading frames (ncORFs) encoded throughout the human genome can be translated into unconventional proteins, several of which are implicated in tumorigenesis through disruption of key regulatory pathways. Although previous studies showed that ncORF-derived peptides are presented by human leukocyte antigen (HLA) class I molecules, their overall contribution to the HLA class I immunopeptidome relative to the canonical proteome remains unclear. We used a database comprising 7, 264 human ncORFs sequences to identify ncORF-derived peptide ligands in mass spectrometry datasets covering 102 HLA class I classical and non-classical alleles to determine their role as parental proteins of HLA class I ligands compared to the canonical proteome. Across these alleles, covering the vast majority of the human population, ncORF-derived ligands represented an average of 2.13% of the total HLA class I ligandome although their representation varied substantially between individual alleles. Notably, HLA class I molecules with Alanine, Proline, or basic as anchor residues displayed a higher proportion of these ncORF-derived peptides, and the C-terminal peptide anchor motif showed the strongest association with ncORF-derived ligand presentation. Likewise, ncORF-derived proteins containing HLA class I-bound epitopes exhibited higher transcript abundance, were more basic and less hydrophilic compared to ncORFs that did not generate class I HLA ligands. Overall, ncORF-derived peptides represented a fraction of the HLA class I ligandome and revealed HLA allele-specific anchor motif preferences shape immunopeptidomic representation. Our results expand the current understanding of the antigenic repertoire landscape of healthy organs and, above all, tumor tissues.
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BibTeX
@article{rivera2026class,
title = {{HLA class I anchor motifs contribute to antigen presentation from non-canonical open reading frames}},
author = {Andrea Rivera and Elena Lorente and Daniel López},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1939526},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1939526/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - HLA class I anchor motifs contribute to antigen presentation from non-canonical open reading frames
AU - Andrea Rivera
AU - Elena Lorente
AU - Daniel López
PY - 2026
DA - 2026/10/22
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1939526
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1939526/full
AB - Non-canonical open reading frames (ncORFs) encoded throughout the human genome can be translated into unconventional proteins, several of which are implicated in tumorigenesis through disruption of key regulatory pathways. Although previous studies showed that ncORF-derived peptides are presented by human leukocyte antigen (HLA) class I molecules, their overall contribution to the HLA class I immunopeptidome relative to the canonical proteome remains unclear. We used a database comprising 7, 264 human ncORFs sequences to identify ncORF-derived peptide ligands in mass spectrometry datasets covering 102 HLA class I classical and non-classical alleles to determine their role as parental proteins of HLA class I ligands compared to the canonical proteome. Across these alleles, covering the vast majority of the human population, ncORF-derived ligands represented an average of 2.13% of the total HLA class I ligandome although their representation varied substantially between individual alleles. Notably, HLA class I molecules with Alanine, Proline, or basic as anchor residues displayed a higher proportion of these ncORF-derived peptides, and the C-terminal peptide anchor motif showed the strongest association with ncORF-derived ligand presentation. Likewise, ncORF-derived proteins containing HLA class I-bound epitopes exhibited higher transcript abundance, were more basic and less hydrophilic compared to ncORFs that did not generate class I HLA ligands. Overall, ncORF-derived peptides represented a fraction of the HLA class I ligandome and revealed HLA allele-specific anchor motif preferences shape immunopeptidomic representation. Our results expand the current understanding of the antigenic repertoire landscape of healthy organs and, above all, tumor tissues.
SN - 1664-3224
ER -