ArticleMolecular & cellular proteomics : MCP2020
Identification of an Unconventional Subpeptidome Bound to the Behçet's Disease-associated HLA-B*51:01 that is Regulated by Endoplasmic Reticulum Aminopeptidase 1 (ERAP1).
Article in Molecular & cellular proteomics : MCP, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 20 citations in OpenAlex.
- A generalizable system for antigenic peptide targeting across HLA-I allotypes.bioRxiv : the preprint server for biology · 2026Article
- Novel genetic variants of HLA gene associated with Thai Behcet's disease (BD) patients using next generation sequencing technology.Scientific reports · 2024Article
- Non-mutational neoantigens in disease.Nature immunology · 2024Review
- SARS-CoV-2 Gut-Targeted Epitopes: Sequence Similarity and Cross-Reactivity Join Together for Molecular Mimicry.Biomedicines · 2023Article
- Behçet's disease risk-variant HLA-B51/ERAP1-Hap10 alters human CD8 T cell immunity.Annals of the rheumatic diseases · 2022Article
- FunctionalCells · 2022Article
- The association of Behçet's syndrome with HLA-B51 as understood in 2021.Current opinion in rheumatology · 2022Review
- Know thy immune self and non-self: Proteomics informs on the expanse of self and non-self, and how and where they arise.Proteomics · 2021Review
- ERAP2 Increases the Abundance of a Peptide Submotif Highly Selective for the Birdshot Uveitis-Associated HLA-A29.Frontiers in immunology · 2021Article
- The Impact of the 'Mis-Peptidome' on HLA Class I-Mediated Diseases: Contribution of ERAP1 and ERAP2 and Effects on the Immune Response.International journal of molecular sciences · 2020Review
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
Abstract
Human leukocyte antigen (HLA) B*51:01 and endoplasmic reticulum aminopeptidase 1 (ERAP1) are strongly genetically associated with Behçet's disease (BD). Previous studies have defined two subgroups of HLA-B*51 peptidome containing proline (Pro) or alanine (Ala) at position 2 (P2). Little is known about the unconventional non-Pro/Ala2 HLA-B*51-bound peptides. We aimed to study the features of this novel subpeptidome, and investigate its regulation by ERAP1. CRISPR-Cas9 was used to generate an HLA-ABC-triple knockout HeLa cell line (HeLa.ABC-KO), which was subsequently transduced to express HLA-B*51:01 (HeLa.ABC-KO.B51). ERAP1 was silenced using lentiviral shRNA. Peptides bound to HLA-B*51:01 were eluted and analyzed by mass spectrometry. The characteristics of non-Pro/Ala2, Pro2, and Ala2 peptides and their alteration by ERAP1 silencing were investigated. Effects of ERAP1 silencing on cell surface expression of HLA-B*51:01 were studied using flow cytometry. More than 20% of peptides eluted from HLA-B*51:01 lacked Pro or Ala at P2. This unconventional group of HLA-B*51:01-bound peptides was relatively enriched for 8-mers (with relatively fewer 9-mers) compared with the Pro2 and Ala2 subpeptidomes and had similar N-terminal and C-terminal residue usages to Ala2 peptides (with the exception of the less abundant leucine at position Ω). Knockdown of ERAP1 increased the percentage of non-Pro/Ala2 from 20% to ∼40%, increased the percentage of longer (10-mer and 11-mer) peptides eluted from HLA-B*51:01 complexes, and abrogated the predominance of leucine at P1. Interestingly knockdown of ERAP1 altered the length and N-terminal residue usage of non-Ala2&Pro2 and Ala2 but not the Pro2 peptides. Finally, ERAP1 silencing regulated the expression levels of cell surface HLA-B*51 in a cell-type-dependent manner. In conclusion, we have used a novel methodology to identify an unconventional but surprisingly abundant non-Pro/Ala2 HLA-B*51:01 subpeptidome. It is increased by knockdown of ERAP1, a gene affecting the risk of developing BD. This has implications for theories of disease pathogenesis.
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