title: Endoplasmic Reticulum Aminopeptidase 1 (ERAP1) Polymorphism Relevant to Inflammatory Disease Shapes the Peptidome of the Birdshot Chorioretinopathy-Associated HLA-A*29:02 Antigen.
abstract: Birdshot chorioretinopathy is a rare ocular inflammation whose genetic association with HLA-A*29:02 is the highest between a disease and a major histocompatibility complex (MHC) molecule. It belongs to a group of MHC-I-associated inflammatory disorders, also including ankylosing spondylitis, psoriasis, and Behçet's disease, for which endoplasmic reticulum aminopeptidases (ERAP) 1 and/or 2 have been identified as genetic risk factors. Since both enzymes are involved in the processing of MHC-I ligands, it seems reasonable that common peptide-mediated mechanisms may underlie the pathogenesis of these diseases. In this study, comparative immunopeptidomics was used to characterize >5000 A*29:02 ligands and quantify the effects of ERAP1 polymorphism and expression on the A*29:02 peptidome in human cells. The peptides predominant in an active ERAP1 context showed a higher frequency of nonamers and bulkier amino acid side chains at multiple positions, compared with the peptides predominant in a less active ERAP1 background. Thus, ERAP1 polymorphism has a large influence, shaping the A*29:02 peptidome through length-dependent and length-independent effects. These changes resulted in increased affinity and hydrophobicity of A*29:02 ligands in an active ERAP1 context. The results reveal the nature of the functional interaction between A*29:02 and ERAP1 and suggest that this enzyme may affect the susceptibility to birdshot chorioretinopathy by altering the A*29:02 peptidome. The complexity of these alterations is such that not only peptide presentation but also other potentially pathogenic features could be affected.
authors.affiliation: From the ‡Centro de Biología Molecular Severo Ochoa (CSIC-UAM), 28049 Madrid, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Alvarez-Navarro
authors.affiliation: From the ‡Centro de Biología Molecular Severo Ochoa (CSIC-UAM), 28049 Madrid, Spain.
authors.forename: Adrian
authors.initials: A
authors.lastname: Martín-Esteban
authors.affiliation: §Faculty of Biology, Technion-Israel Institute of Technology, Haifa 32000, Israel.
authors.forename: Eilon
authors.initials: E
authors.lastname: Barnea
authors.affiliation: §Faculty of Biology, Technion-Israel Institute of Technology, Haifa 32000, Israel.
authors.forename: Arie
authors.initials: A
authors.lastname: Admon
authors.affiliation: From the ‡Centro de Biología Molecular Severo Ochoa (CSIC-UAM), 28049 Madrid, Spain. aldecastro@cbm.csic.es.
authors.forename: José A
authors.initials: JA
authors.lastname: López de Castro
mesh_terms: D000626:Aminopeptidases / Q000235:genetics*; D000080365:Birdshot Chorioretinopathy; D002460:Cell Line; D002825:Chorioretinitis / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D015234:HLA-A Antigens / Q000235:genetics*; D006801:Humans; D007249:Inflammation / Q000235:genetics*; D008024:Ligands; D015778:Minor Histocompatibility Antigens; D010455:Peptides / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D020543:Proteome / Q000378:metabolism*
chemical_list: D015234:HLA-A Antigens; C520711:HLA-A*29:02 antigen; D008024:Ligands; D015778:Minor Histocompatibility Antigens; D010455:Peptides; D020543:Proteome; D000626:Aminopeptidases; C464841:ERAP1 protein, human; C503944:ERAP2 protein, human