Please use this identifier to cite or link to this item:http://hdl.handle.net/20.500.12105/12830
Title
Substantial Influence of ERAP2 on the HLA-B*40:02 Peptidome: Implications for HLA-B*27-Negative Ankylosing Spondylitis.
Author(s)
Lorente, Elena ISCIII | Redondo-Anton, Jennifer ISCIII | Martín-Esteban, Adrian | Guasp, Pablo | Barnea, Eilon | Lauzurica, Pilar ISCIII | Admon, Arie | López de Castro, José A
Date issued
2019
Citation
Mol Cell Proteomics. 2019;18(11):2298-2309.
Language
Inglés
Document type
journal article
Abstract
HLA-B*40:02 is one of a few major histocompatibility complex class I (MHC-I) molecules associated with ankylosing spondylitis (AS) independently of HLA-B*27. The endoplasmic reticulum aminopeptidase 2 (ERAP2), an enzyme that process MHC-I ligands and preferentially trims N-terminal basic residues, is also a risk factor for this disease. Like HLA-B*27 and other AS-associated MHC-I molecules, HLA-B*40:02 binds a relatively high percentage of peptides with ERAP2-susceptible residues. In this study, the effects of ERAP2 depletion on the HLA-B*40:02 peptidome were analyzed. ERAP2 protein expression was knocked out by CRISPR in the transfectant cell line C1R-B*40:02, and the differences between the peptidomes from the wild-type and ERAP2-KO cells were determined by label-free quantitative comparisons. The qualitative changes dependent on ERAP2 affected about 5% of the peptidome, but quantitative changes in peptide amounts were much more substantial, reflecting a significant influence of this enzyme on the generation/destruction balance of HLA-B*40:02 ligands. As in HLA-B*27, a major effect was on the frequencies of N-terminal residues. In this position, basic and small residues were increased, and aliphatic/aromatic ones decreased in the ERAP2 knockout. Other peptide positions were also affected. Because most of the non-B*27 MHC-I molecules associated with AS risk bind a relatively high percentage of peptides with N-terminal basic residues, we hypothesize that the non-epistatic association of ERAP2 with AS might be related to the processing of peptides with these residues, thus affecting the peptidomes of AS-associated MHC-I molecules.
Subject
Ankylosing Spondylitis | ERAP2 | Enzyme Mechanisms | HLA-B*40 | Immunology | Inflammation | Label-Free Quantification | Peptidomics
MESH
Aminopeptidases | CRISPR-Cas Systems | HLA-B Antigens | HLA-B27 Antigen | Humans | Peptide Fragments | Protein Binding | Proteome | Spondylitis, Ankylosing
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