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 Behç et'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.

Effects of polymorphic variation on the mechanism of Endoplasmic Reticulum Aminopeptidase 1

“…Mutations away from the active site should be much easier to tolerate since they should not lead to completely inactive enzyme. Sampling different locations for variation allows the immune system to generate an array of different ERAP1 activities that we now know they can affect immunodominance and responses to disease (Alvarez-Navarro and Lopez de Castro, 2014; Reeves et al, 2013;Sanz-Bravo et al, 2015;Alvarez-Navarro et al, 2015). Indeed, recent work has been slowly revealing that ERAP1 samples a highly dynamic range of activities in different individuals, from hypertrimming to hypo-trimming, affecting adaptive immune responses .…”

“…Several studies have also demonstrated that these disease-associated variants affect ERAP1 enzymatic activity and selectivity, cellular antigen presentation and concomitant cytotoxic responses Chen et al, 2014;Reeves et al, 2013;Garcia-Medel et al, 2012;Sanz-Bravo et al, 2015;Alvarez-Navarro et al, 2015;Martin-Esteban et al, 2014). Interestingly, in several of those studies, changes in ERAP1 activity due to polymorphic variation at positions 528 and 730 have been correlated with the production of different lengths of antigenic peptides although the effects of peptide sequence were not investigated in those studies (Garcia-Medel et al, 2012;Sanz-Bravo et al, 2015;Alvarez-Navarro et al, 2015). Specific ERAP1 haplotypes have been proposed to constitute a range of different activities that correlate to disease predisposition Seregin et al, 2013).…”

ERAAP Shapes the Peptidome Associated with Classical and Nonclassical MHC Class I Molecules

“…Polymorphic variants of human ERAAP have been associated with a variety of autoimmune diseases (6–11), suggesting that ERAAP strongly influences the peptides presented by MHC I molecules. Indeed, changes in the pMHC I repertoire associated with ERAP1 polymorphisms have been found (12). …”

ERAP1 molecular characterization: Identification of a de novo allelic variant

“…Several class I human leukocyte antigen (HLA) alleles are associated with inflammatory diseases, such as Behçet syndrome (BS; HLA‐B*51 ), ankylosing spondylitis (AS; HLA‐B*27 ) and psoriasis (Pso; HLA‐C*06:02 ). Non‐HLA alleles were also reported as disease risk factors and in particular the endoplasmic reticulum aminopeptidase protein 1 (ERAP1) acting in epistasis with the predisposing HLA alleles . The ERAP1 gene is located on chromosome 5q15 and it encodes the enzyme that trims the N‐terminal peptides optimizing their length for HLA binding.…”